rs199573929

Variant names:

Variant summary

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

The NM_015120.4(ALMS1):c.2036A>G(p.Tyr679Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,872 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

ALMS1
NM_015120.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:7

Conservation

PhyloP100: -0.105

Publications

4 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:

ENSG00000295621 (HGNC:):

ENSG00000295621 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=0.015712231).

BP6

Variant 2-73448563-A-G is Benign according to our data. Variant chr2-73448563-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210126.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00149 (227/152150) while in subpopulation SAS AF = 0.00269 (13/4826). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015120.4. 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.2036A>G	p.Tyr679Cys	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.2036A>G	p.Tyr679Cys	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.2036A>G	p.Tyr679Cys	missense	Exon 8 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.1910A>G	p.Tyr637Cys	missense	Exon 7 of 22	ENSP00000478155.1
ALMS1	ENST00000684548.1		c.1655A>G	p.Tyr552Cys	missense	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00157

AC:

390

AN:

248830

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.000388

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000835

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00251

AC:

3669

AN:

1461722

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1839

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33464

American (AMR)

AF:

0.000380

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00284

AC:

245

AN:

86256

European-Finnish (FIN)

AF:

0.000636

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00292

AC:

3250

AN:

1111916

Other (OTH)

AF:

0.00169

AC:

102

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

240

480

719

959

1199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00149

AC:

227

AN:

152150

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000555

AC:

AN:

41478

American (AMR)

AF:

0.000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00269

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00253

AC:

172

AN:

67988

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00221

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00163

AC:

197

EpiCase

AF:

0.00180

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alstrom syndrome (7)

not provided (4)

not specified (3)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.038

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.51

M_CAP

Benign

0.0047

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

PhyloP100

-0.10

PrimateAI

Benign

0.38

Sift4G

Benign

0.11

Vest4

0.57

MVP

0.21

ClinPred

0.036

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.19

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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