rs377281121

Variant names:

• chr2-73424526-C-T
• rs377281121
• NM_001378454.1:c.861C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001378454.1(ALMS1):​c.861C>T​(p.Asp287Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,611,382 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.130
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-73424526-C-T is Benign according to our data. Variant chr2-73424526-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529405.
• BP7: Synonymous conserved (PhyloP=-0.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00025 (38/152188) while in subpopulation AMR AF = 0.00137 (21/15286). AF 95% confidence interval is 0.00092. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.861C>T	p.Asp287Asp	synonymous	Exon 5 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.861C>T	p.Asp287Asp	synonymous	Exon 5 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.861C>T	p.Asp287Asp	synonymous	Exon 5 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.735C>T	p.Asp245Asp	synonymous	Exon 4 of 22	ENSP00000478155.1
	ALMS1	ENST00000684548.1		c.411C>T	p.Asp137Asp	synonymous	Exon 3 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000133 AC: 33 AN: 247824 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000228 AC: 332 AN: 1459194 Hom.: 1 Cov.: 31 AF XY: 0.000205 AC XY: 149 AN XY: 725510

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.000135 AC: 6 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000287 AC: 319 AN: 1110460

Other (OTH) AF: 0.0000332 AC: 2 AN: 60262

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00137 AC: 21 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000204

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	Alstrom syndrome (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.2
DANN	Benign	0.42
PhyloP100		-0.13
Mutation Taster		=99/1	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: rs377281121; hg19: chr2-73651654;