rs186449817

Positions:

• chr2-73450469-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378454.1(ALMS1):​c.3942A>C​(p.Ser1314Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,770 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.490

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-73450469-A-C is Benign according to our data. Variant chr2-73450469-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 240994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000698 (106/151946) while in subpopulation NFE AF= 0.00105 (71/67940). AF 95% confidence interval is 0.000849. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.3942A>C	p.Ser1314Ser	synonymous_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.3942A>C	p.Ser1314Ser	synonymous_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.3942A>C	p.Ser1314Ser	synonymous_variant	8/23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.000698 AC: 106 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000850 AC: 212 AN: 249316 Hom.: 0 AF XY: 0.000954 AC XY: 129 AN XY: 135258

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000790 AC: 1155 AN: 1461824 Hom.: 2 Cov.: 40 AF XY: 0.000831 AC XY: 604 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000773

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000698 AC: 106 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.000660 AC XY: 49 AN XY: 74274

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000946 Hom.: 1

Bravo AF: 0.000646

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	ALMS1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 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. -

Alstrom syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.54
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs186449817; hg19: chr2-73677596;