chr2-73490404-A-G

Variant names:

• chr2-73490404-A-G
• rs137932254
• NM_001378454.1:c.8445A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001378454.1(ALMS1):​c.8445A>G​(p.Ser2815Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,158 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).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 1.37
• Publications: 0 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-73490404-A-G is Benign according to our data. Variant chr2-73490404-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241013.
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00216 (329/152356) while in subpopulation NFE AF = 0.00366 (249/68024). AF 95% confidence interval is 0.00329. There are 1 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.8445A>G	p.Ser2815Ser	synonymous	Exon 10 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.8445A>G	p.Ser2815Ser	synonymous	Exon 10 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.8445A>G	p.Ser2815Ser	synonymous	Exon 10 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.8319A>G	p.Ser2773Ser	synonymous	Exon 9 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000423048.5	TSL:1	n.3030+246A>G		intron	N/A	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00197 AC: 490 AN: 249138 AF XY: 0.00202

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00285 AC: 4162 AN: 1461802 Hom.: 5 Cov.: 32 AF XY: 0.00281 AC XY: 2045 AN XY: 727190

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86252

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53360

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00333 AC: 3704 AN: 1111994

Other (OTH) AF: 0.00177 AC: 107 AN: 60396

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74512

African (AFR) AF: 0.000505 AC: 21 AN: 41590

American (AMR) AF: 0.000915 AC: 14 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4834

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00366 AC: 249 AN: 68024

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00267 Hom.: 0

Bravo AF: 0.00202

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	Alstrom syndrome (5)
-	1	4	not provided (5)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.7
DANN	Benign	0.77
PhyloP100		1.4
Mutation Taster		=97/3	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: rs137932254; hg19: chr2-73717531;