chr2-73449838-G-A

Variant names:

• chr2-73449838-G-A
• rs201074268
• NM_001378454.1:c.3311G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.3311G>A​(p.Gly1104Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,028 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1104S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.53
• Publications: 4 publications found

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048203766).
• BP6: Variant 2-73449838-G-A is Benign according to our data. Variant chr2-73449838-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 387328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (305/152232) while in subpopulation NFE AF = 0.00284 (193/68010). AF 95% confidence interval is 0.00251. There are 1 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.3311G>A	p.Gly1104Asp	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.3311G>A	p.Gly1104Asp	missense	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.3311G>A	p.Gly1104Asp	missense	Exon 8 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.3185G>A	p.Gly1062Asp	missense	Exon 7 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.2930G>A	p.Gly977Asp	missense	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 305 AN: 152114 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00188 AC: 468 AN: 248562 AF XY: 0.00197

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00385

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00285 AC: 4172 AN: 1461796 Hom.: 10 Cov.: 39 AF XY: 0.00271 AC XY: 1971 AN XY: 727202

African (AFR) AF: 0.000478 AC: 16 AN: 33470

American (AMR) AF: 0.00125 AC: 56 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86254

European-Finnish (FIN) AF: 0.00346 AC: 185 AN: 53412

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00331 AC: 3679 AN: 1111954

Other (OTH) AF: 0.00278 AC: 168 AN: 60392

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152232 Hom.: 1 Cov.: 33 AF XY: 0.00231 AC XY: 172 AN XY: 74438

African (AFR) AF: 0.000626 AC: 26 AN: 41526

American (AMR) AF: 0.00196 AC: 30 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00246 Hom.: 4

Bravo AF: 0.00187

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00256 AC: 21

ExAC AF: 0.00168 AC: 203

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ALMS1: BP4

Alstrom syndrome Benign:3

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs201074268 in Alstrom syndrome yet.

not specified Benign:2

Dec 26, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 06, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALMS1 c.3308G>A/p.Gly1103Asp (also known as c.3314G>A in RefSeq) results in a non-conservative amino acid change located in the Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 248562 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although the variant has been reported in a paper describing the mutational spectrum of Alstrom syndrome, this publication provides no primary evidence supporting a pathogenic outcome (Marshall_2015). To our knowledge, no occurrence of c.3308G>A in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TTR c.424G>A , p.Val1421Ile), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

Monogenic diabetes Benign:1

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BP4 (8 predictors + REVEL score 0.117), BS2 (1 homozygotes in gnomAD), BP1 (missense when truncating are cause of disease)= benign

Cardiovascular phenotype Benign:1

Jan 26, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0020
DANN	Benign	0.30
DEOGEN2	Benign	0.014	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.038	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.95	T
PhyloP100		-4.5
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.48	T
Vest4		0.14
MVP		0.088
ClinPred		0.0075	T
GERP RS		-8.9
PromoterAI		-0.0094	Neutral
Varity_R		0.055
gMVP		0.040
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201074268; hg19: chr2-73676965; COSMIC: COSV52507753; COSMIC: COSV52507753;