rs61741524

chr2-73600830-G-Achr2-73600830-G-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.11821G>A(p.Gly3941Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,614,176 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3941C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (8 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0570

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=0.0047307312).
• BP6: Variant 2-73600830-G-A is Benign according to our data. Variant chr2-73600830-G-A is described in ClinVar as [Benign]. Clinvar id is 194868.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 = 0.00391 (595/152316) while in subpopulation AFR AF= 0.0124 (514/41582). AF 95% confidence interval is 0.0115. There are 8 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.11821G>A	p.Gly3941Ser	missense_variant	18/23	ENST00000613296.6
ALMS1	NM_015120.4	c.11824G>A	p.Gly3942Ser	missense_variant	18/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.11821G>A	p.Gly3941Ser	missense_variant	18/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152198 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00115 AC: 289 AN: 251190 Hom.: 4 AF XY: 0.00107 AC XY: 145 AN XY: 135824

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000534 AC: 780 AN: 1461860 Hom.: 8 Cov.: 31 AF XY: 0.000546 AC XY: 397 AN XY: 727236

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152316 Hom.: 8 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74470

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00467

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 166

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 16, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	p.Gly3940Ser in exon 18 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 1.30% (309/24020) of African chro mosomes including 4 homozygotes by the Genome Aggregation Database (gnomAD, http ://gnomAD.broadinstitute.org; dbSNP rs61741524). ACMG/AMP criteria applied: BA1 . -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2018	Variant summary: ALMS1 c.11818G>A (p.Gly3940Ser, alternative name c.11824G>A) 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 0.0014 in 277116 control chromosomes, predominantly within the African subpopulation at a frequency of 0.013 in the gnomAD database, including 4 homozygotes. The observed variant frequency within African control individuals is approximately 5.8 fold above 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 origin. c.11818G>A has been reported in the literature in patients with clinical features of Alstrom syndrome. But this report does not provide unequivocal conclusions about association of the variant with cardiomyopathy or with Alstrom syndrome and is listed among a series of SNV's that were deemed as being unlikely to be pathogenic by the authors. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and 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)	Aug 27, 2014	- -

Alstrom syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
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 rs61741524 in Alstrom syndrome yet. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 15, 2019

ACMG criteria: BP4 (9 predictors, Revel score 0.031), BA1 (1.3% in gnomAD African) , BP1, BS2 (4 homozygotes in gnomAD African)= benign -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2019

This alteration is classified as 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	0.068
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.019
Dann	Benign	0.28
DEOGEN2	Benign	0.0051	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.71	T;T
Vest4		0.11
MVP		0.076
ClinPred		0.0010	T
GERP RS		-3.9
Varity_R		0.020
gMVP		0.038

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61741524; hg19: chr2-73827957;