rs142022233

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.9914A>G(p.Asn3305Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00356 in 1,614,066 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts 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. N3305I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 65 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.18

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008951098).

BP6

Variant 2-73550273-A-G is Benign according to our data. Variant chr2-73550273-A-G is described in ClinVar as Benign. ClinVar VariationId is 393379.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 = 0.00236 (359/152306) while in subpopulation SAS AF = 0.024 (116/4828). AF 95% confidence interval is 0.0205. There are 2 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.9914A>G	p.Asn3305Ser	missense	Exon 13 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.9914A>G	p.Asn3305Ser	missense	Exon 13 of 23	NP_055935.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.9914A>G	p.Asn3305Ser	missense	Exon 13 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.9788A>G	p.Asn3263Ser	missense	Exon 12 of 22	ENSP00000478155.1
ALMS1	ENST00000423048.5	TSL:1	n.*333A>G		non_coding_transcript_exon	Exon 6 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

356

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00248

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00534

AC:

1332

AN:

249250

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00244

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.000780

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00319

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00368

AC:

5384

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

3265

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33476

American (AMR)

AF:

0.00300

AC:

134

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

26128

East Asian (EAS)

AF:

0.000479

AC:

AN:

39694

South Asian (SAS)

AF:

0.0270

AC:

2330

AN:

86226

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00222

AC:

2472

AN:

1111958

Other (OTH)

AF:

0.00386

AC:

233

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

246

491

737

982

1228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00236

AC:

359

AN:

152306

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

193

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41566

American (AMR)

AF:

0.00235

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3466

East Asian (EAS)

AF:

0.00116

AC:

AN:

5186

South Asian (SAS)

AF:

0.0240

AC:

116

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00248

AC:

169

AN:

68022

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

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:

0.00263

Hom.:

Bravo

AF:

0.00184

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00448

AC:

ExAC

AF:

0.00596

AC:

720

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00445

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Alstrom syndrome (2)

not provided (2)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.2

PhyloP100

4.2

PrimateAI

Benign

0.47

Sift4G

Benign

0.45

Vest4

0.40

MVP

0.39

ClinPred

0.048

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.25

Mutation Taster

=94/6

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over