rs10193972

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.8570A>G(p.Asn2857Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,613,888 control chromosomes in the GnomAD database, including 65,469 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 Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 15449 hom., cov: 32)

Exomes 𝑓: 0.24 ( 50020 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.502

Publications

41 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.000128E-7).

BP6

Variant 2-73490529-A-G is Benign according to our data. Variant chr2-73490529-A-G is described in ClinVar as Benign. ClinVar VariationId is 383762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

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.8570A>G	p.Asn2857Ser	missense	Exon 10 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.8570A>G	p.Asn2857Ser	missense	Exon 10 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.8570A>G	p.Asn2857Ser	missense	Exon 10 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.8444A>G	p.Asn2815Ser	missense	Exon 9 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000423048.5	TSL:1	n.3030+371A>G		intron	N/A	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes

AF:

0.382

AC:

57998

AN:

151998

Hom.:

15390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.755

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.00694

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.334

GnomAD2 exomes

AF:

0.263

AC:

65538

AN:

249012

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.770

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.00607

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.239

GnomAD4 exome

AF:

0.242

AC:

354219

AN:

1461772

Hom.:

50020

Cov.:

AF XY:

0.238

AC XY:

173213

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.766

AC:

25658

AN:

33480

American (AMR)

AF:

0.407

AC:

18189

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3959

AN:

26134

East Asian (EAS)

AF:

0.0122

AC:

485

AN:

39698

South Asian (SAS)

AF:

0.167

AC:

14419

AN:

86256

European-Finnish (FIN)

AF:

0.231

AC:

12351

AN:

53374

Middle Eastern (MID)

AF:

0.244

AC:

1407

AN:

5768

European-Non Finnish (NFE)

AF:

0.236

AC:

262889

AN:

1111946

Other (OTH)

AF:

0.246

AC:

14862

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

16713

33427

50140

66854

83567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9016

18032

27048

36064

45080

<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:

0.382

AC:

58120

AN:

152116

Hom.:

15449

Cov.:

AF XY:

0.375

AC XY:

27904

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.755

AC:

31340

AN:

41494

American (AMR)

AF:

0.371

AC:

5673

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

550

AN:

3472

East Asian (EAS)

AF:

0.00696

AC:

AN:

5176

South Asian (SAS)

AF:

0.151

AC:

727

AN:

4818

European-Finnish (FIN)

AF:

0.242

AC:

2560

AN:

10566

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16229

AN:

67988

Other (OTH)

AF:

0.330

AC:

697

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1401

2802

4203

5604

7005

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.281

Hom.:

26321

Bravo

AF:

0.410

TwinsUK

AF:

0.228

AC:

847

ALSPAC

AF:

0.232

AC:

895

ESP6500AA

AF:

0.725

AC:

2743

ESP6500EA

AF:

0.237

AC:

1947

ExAC

AF:

0.266

AC:

32118

Asia WGS

AF:

0.124

AC:

430

AN:

3478

EpiCase

AF:

0.231

EpiControl

AF:

0.236

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Alstrom syndrome (3)

Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.3

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.40

MetaRNN

Benign

8.0e-7

MetaSVM

Benign

-1.1

PhyloP100

-0.50

PrimateAI

Benign

0.32

Sift4G

Benign

0.61

Vest4

0.011

ClinPred

0.0034

GERP RS

0.23

Varity_R

0.058

gMVP

0.0026

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over