2-73534928-A-G

Position:

• chr2-73534928-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378454.1(ALMS1):​c.9886A>G​(p.Thr3296Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000483 in 1,613,806 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T3296T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 5.24

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008086473).
• BP6: Variant 2-73534928-A-G is Benign according to our data. Variant chr2-73534928-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Uncertain_risk_allele=1, Benign=5}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00269 (409/152308) while in subpopulation AFR AF= 0.00936 (389/41568). AF 95% confidence interval is 0.00859. There are 4 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.9886A>G	p.Thr3296Ala	missense_variant	12/23	ENST00000613296.6
ALMS1	NM_015120.4	c.9889A>G	p.Thr3297Ala	missense_variant	12/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.9886A>G	p.Thr3296Ala	missense_variant	12/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152190 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00939

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000634 AC: 158 AN: 249334 Hom.: 2 AF XY: 0.000414 AC XY: 56 AN XY: 135264

Gnomad AFR exome AF: 0.00975

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1461498 Hom.: 2 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 727066

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152308 Hom.: 4 Cov.: 33 AF XY: 0.00256 AC XY: 191 AN XY: 74474

Gnomad4 AFR AF: 0.00936

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000584 Hom.: 2

Bravo AF: 0.00314

ESP6500AA AF: 0.00827 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000770 AC: 93

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Uncertain significance, flagged submission	clinical testing	GeneDx	Nov 21, 2016	A variant of uncertain significance has been identified in the ALMS1 gene. The T3297A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T3297A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, the Exome Aggregation Consortium (ExAC) reports T3297A was observed in 91/9,788 (0.9%) alleles from individuals of African background, including one homozygous individual, indicating it may be a rare benign variant in this population. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Thr3295Ala in exon 12 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.93% (91/9788) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs58806616). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2019	Variant summary: ALMS1 c.9883A>G (p.Thr3295Ala, also known as c.9889A>G) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 249334 control chromosomes, predominantly at a frequency of 0.0098 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.9883A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classified it as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign. -

Alstrom syndrome Benign:2 Other:1

Uncertain risk allele, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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 rs58806616 in Alstrom syndrome yet. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 01, 2020	- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 16, 2018

ACMG criteria: PP3 (6 predictors), BP4 (3 predictors), BS1 (1.13% in 1000G African population and disease frequency is 1 in 10,000), BS2 (4 homozygotes in gnomAD)=benign -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T;T
MetaRNN	Benign	0.0081	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.87	N;N
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.091	T;T;D
Vest4		0.59
MVP		0.42
ClinPred		0.086	T
GERP RS		4.8
Varity_R		0.054
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs58806616; hg19: chr2-73762055;