rs58093963

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378454.1(ALMS1):c.6464A>G(p.Asp2155Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,612,596 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 13 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.62

Publications

7 publications found

Variant links:

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

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026153028).

BP6

Variant 2-73452991-A-G is Benign according to our data. Variant chr2-73452991-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235595.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.004 (609/152274) while in subpopulation AFR AF = 0.0122 (506/41556). AF 95% confidence interval is 0.0113. There are 5 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.6464A>G	p.Asp2155Gly	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.6464A>G	p.Asp2155Gly	missense	Exon 8 of 23	NP_055935.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.6464A>G	p.Asp2155Gly	missense	Exon 8 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.6338A>G	p.Asp2113Gly	missense	Exon 7 of 22	ENSP00000478155.1
ALMS1	ENST00000423048.5	TSL:1	n.1295A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

604

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00211

AC:

522

AN:

247636

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.0192

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000276

Gnomad OTH exome

AF:

0.00333

GnomAD4 exome

AF:

0.000857

AC:

1252

AN:

1460322

Hom.:

Cov.:

AF XY:

0.000815

AC XY:

592

AN XY:

726334

show subpopulations

African (AFR)

AF:

0.0141

AC:

470

AN:

33404

American (AMR)

AF:

0.00224

AC:

100

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0174

AC:

454

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52904

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

1111358

Other (OTH)

AF:

0.00227

AC:

137

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

151

226

302

377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00400

AC:

609

AN:

152274

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0122

AC:

506

AN:

41556

American (AMR)

AF:

0.00183

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68008

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00468

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.00122

AC:

ExAC

AF:

0.00213

AC:

257

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Alstrom syndrome (3)

not specified (2)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.085

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

PhyloP100

2.6

PrimateAI

Benign

0.31

Sift4G

Uncertain

0.028

Vest4

0.23

MVP

0.099

ClinPred

0.0078

GERP RS

1.9

Varity_R

0.036

gMVP

0.11

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over