rs144486524

chr2-73572628-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):c.10751A>T(p.Gln3584Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,614,090 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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. Q3584E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.425

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055217743).
• BP6: Variant 2-73572628-A-T is Benign according to our data. Variant chr2-73572628-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 235538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00286 (436/152362) while in subpopulation AFR AF= 0.00991 (412/41590). AF 95% confidence interval is 0.00912. There are 4 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.10751A>T	p.Gln3584Leu	missense_variant	16/23	ENST00000613296.6
ALMS1	NM_015120.4	c.10754A>T	p.Gln3585Leu	missense_variant	16/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.10751A>T	p.Gln3584Leu	missense_variant	16/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 436 AN: 152244 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000659 AC: 164 AN: 248684 Hom.: 2 AF XY: 0.000482 AC XY: 65 AN XY: 134918

Gnomad AFR exome AF: 0.00944

Gnomad AMR exome AF: 0.000436

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: 0.0000177

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000267 AC: 390 AN: 1461728 Hom.: 3 Cov.: 32 AF XY: 0.000230 AC XY: 167 AN XY: 727162

Gnomad4 AFR exome AF: 0.00917

Gnomad4 AMR exome AF: 0.000537

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: 0.00000450

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152362 Hom.: 4 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74500

Gnomad4 AFR AF: 0.00991

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.00317

ESP6500AA AF: 0.00998 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000728 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gln3583Leu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.87% (84/9696) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144486524). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2021	Variant summary: ALMS1 c.10748A>T (p.Gln3583Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 248684 control chromosomes, predominantly at a frequency of 0.0094 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 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.10748A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ALMS1: BP4, BS2 -

Alstrom syndrome Benign:2

Likely benign, 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 rs144486524 in Alstrom syndrome yet. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 09, 2018

ACMG criteria: BS2 (type2diabetesgenetics.org), BP4 (6 predictors), BP1 (most causal variants are truncating variants), Note:similar MAF in TODAY/1000G=likely benign -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 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	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	6.0
Dann	Benign	0.86
DEOGEN2	Benign	0.047	T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.34	T;T;T
Vest4		0.17
MVP		0.12
ClinPred		0.0068	T
GERP RS		-1.3
Varity_R		0.042
gMVP		0.090

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: rs144486524; hg19: chr2-73799755;