rs45630557

Variant names:

• chr2-73426482-G-A
• rs45630557
• NM_001378454.1:c.1267G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-73426482-G-A
• chr2-73426482-G-C
• chr2-73426482-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.1267G>A​(p.Val423Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,614,050 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. V423L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (24 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.251
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004122615).
• BP6: Variant 2-73426482-G-A is Benign according to our data. Variant chr2-73426482-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0029 (441/152280) while in subpopulation SAS AF = 0.00643 (31/4824). AF 95% confidence interval is 0.00465. There are 1 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 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.1267G>A	p.Val423Ile	missense	Exon 6 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.1267G>A	p.Val423Ile	missense	Exon 6 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.1267G>A	p.Val423Ile	missense	Exon 6 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.1141G>A	p.Val381Ile	missense	Exon 5 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.817G>A	p.Val273Ile	missense	Exon 4 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00290 AC: 722 AN: 249394 AF XY: 0.00312

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00357

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00398 AC: 5821 AN: 1461770 Hom.: 24 Cov.: 31 AF XY: 0.00400 AC XY: 2907 AN XY: 727192

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00538 AC: 464 AN: 86256

European-Finnish (FIN) AF: 0.00283 AC: 151 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00442 AC: 4916 AN: 1111910

Other (OTH) AF: 0.00349 AC: 211 AN: 60390

GnomAD4 genome AF: 0.00290 AC: 441 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74454

African (AFR) AF: 0.000842 AC: 35 AN: 41570

American (AMR) AF: 0.000720 AC: 11 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4824

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00469 AC: 319 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00371 Hom.: 3

Bravo AF: 0.00257

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00129 AC: 5

ESP6500EA AF: 0.00423 AC: 35

ExAC AF: 0.00258 AC: 312

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (4)
-	-	2	Alstrom syndrome (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hearing impairment (1)
-	-	1	Monogenic diabetes (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.018
DANN	Benign	0.72
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.25
PrimateAI	Benign	0.25	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.17
ClinPred		0.0014	T
GERP RS		0.20
Varity_R		0.010
gMVP		0.0070
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs45630557; hg19: chr2-73653610; COSMIC: COSV52525837;