rs61741524

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.11821G>A(p.Gly3941Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000852 in 1,614,176 control chromosomes in the GnomAD database, including 16 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3941C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 8 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.0570

Publications

3 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=0.0047307312).

BP6

Variant 2-73600830-G-A is Benign according to our data. Variant chr2-73600830-G-A is described in ClinVar as Benign. ClinVar VariationId is 194868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00391 (595/152316) while in subpopulation AFR AF = 0.0124 (514/41582). AF 95% confidence interval is 0.0115. There are 8 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR,Unknown 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.11821G>A	p.Gly3941Ser	missense	Exon 18 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.11821G>A	p.Gly3941Ser	missense	Exon 18 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.11821G>A	p.Gly3941Ser	missense	Exon 18 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.11695G>A	p.Gly3899Ser	missense	Exon 17 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000684548.1		c.11440G>A	p.Gly3814Ser	missense	Exon 16 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes

AF:

0.00391

AC:

595

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00115

AC:

289

AN:

251190

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000534

AC:

780

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000546

AC XY:

397

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0132

AC:

443

AN:

33478

American (AMR)

AF:

0.00116

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00111

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000908

AC:

101

AN:

1111990

Other (OTH)

AF:

0.00109

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00391

AC:

595

AN:

152316

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0124

AC:

514

AN:

41582

American (AMR)

AF:

0.00353

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68028

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

148

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:

0.00235

Hom.:

Bravo

AF:

0.00467

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00137

AC:

166

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Alstrom syndrome (4)

not provided (4)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.019

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.0051

Eigen

Benign

-2.0

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.94

PhyloP100

0.057

PrimateAI

Benign

0.27

Sift4G

Benign

0.71

Vest4

0.11

MVP

0.076

ClinPred

0.0010

GERP RS

-3.9

Varity_R

0.020

gMVP

0.038

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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