dbSNP rs1881245: ALMS1:c.647-57G>A (chr2-73422800-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001378454.1(ALMS1):c.647-57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,349,096 control chromosomes in the GnomAD database, including 52,567 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.36 ( 13269 hom., cov: 31)

Exomes 𝑓: 0.24 ( 39298 hom. )

Consequence

ALMS1
NM_001378454.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.221

Publications

15 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.647-57G>A		intron_variant	Intron 3 of 22	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.647-57G>A		intron_variant	Intron 3 of 22		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.647-57G>A		intron_variant	Intron 3 of 22	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

54702

AN:

151686

Hom.:

13213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.688

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.359

Gnomad ASJ

AF:

0.149

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.140

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.319

GnomAD4 exome

AF:

0.238

AC:

285528

AN:

1197294

Hom.:

39298

AF XY:

0.234

AC XY:

142155

AN XY:

608516

show subpopulations

African (AFR)

AF:

0.697

AC:

19511

AN:

27982

American (AMR)

AF:

0.401

AC:

17685

AN:

44146

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

3467

AN:

24376

East Asian (EAS)

AF:

0.0122

AC:

465

AN:

38050

South Asian (SAS)

AF:

0.152

AC:

12263

AN:

80552

European-Finnish (FIN)

AF:

0.230

AC:

12044

AN:

52268

Middle Eastern (MID)

AF:

0.229

AC:

1200

AN:

5242

European-Non Finnish (NFE)

AF:

0.237

AC:

206520

AN:

873096

Other (OTH)

AF:

0.240

AC:

12373

AN:

51582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

10386

20772

31158

41544

51930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6384

12768

19152

25536

31920

<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:

0.361

AC:

54817

AN:

151802

Hom.:

13269

Cov.:

AF XY:

0.355

AC XY:

26306

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.688

AC:

28486

AN:

41386

American (AMR)

AF:

0.360

AC:

5489

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

516

AN:

3468

East Asian (EAS)

AF:

0.00715

AC:

AN:

5178

South Asian (SAS)

AF:

0.140

AC:

672

AN:

4804

European-Finnish (FIN)

AF:

0.243

AC:

2554

AN:

10494

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.237

AC:

16092

AN:

67908

Other (OTH)

AF:

0.316

AC:

665

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1471

2943

4414

5886

7357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.270

Hom.:

23250

Bravo

AF:

0.386

Asia WGS

AF:

0.112

AC:

389

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.8

(source)

DANN

Benign

0.70

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over