rs28730853

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.4962G>T(p.Lys1654Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,614,006 control chromosomes in the GnomAD database, including 935 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 125 hom., cov: 32)

Exomes 𝑓: 0.013 ( 810 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.250

Publications

8 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=0.0015060306).

BP6

Variant 2-73451489-G-T is Benign according to our data. Variant chr2-73451489-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 389386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0841 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.4962G>T	p.Lys1654Asn	missense	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.4962G>T	p.Lys1654Asn	missense	Exon 8 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.4962G>T	p.Lys1654Asn	missense	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.4836G>T	p.Lys1612Asn	missense	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000684548.1		c.4581G>T	p.Lys1527Asn	missense	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3344

AN:

152088

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0308

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0876

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0212

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00621

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0323

AC:

8044

AN:

248846

AF XY:

0.0252

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.178

Gnomad ASJ exome

AF:

0.00269

Gnomad EAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.0247

GnomAD4 exome

AF:

0.0126

AC:

18473

AN:

1461800

Hom.:

810

Cov.:

AF XY:

0.0117

AC XY:

8475

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0302

AC:

1012

AN:

33470

American (AMR)

AF:

0.168

AC:

7491

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26136

East Asian (EAS)

AF:

0.00801

AC:

318

AN:

39698

South Asian (SAS)

AF:

0.00361

AC:

311

AN:

86256

European-Finnish (FIN)

AF:

0.0183

AC:

975

AN:

53408

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00681

AC:

7569

AN:

1111972

Other (OTH)

AF:

0.0116

AC:

702

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1188

2377

3565

4754

5942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.0221

AC:

3360

AN:

152206

Hom.:

125

Cov.:

AF XY:

0.0235

AC XY:

1750

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0309

AC:

1281

AN:

41522

American (AMR)

AF:

0.0880

AC:

1346

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00270

AC:

AN:

5182

South Asian (SAS)

AF:

0.00498

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0212

AC:

225

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00621

AC:

422

AN:

67998

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

154

309

463

618

772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0106

Hom.:

Bravo

AF:

0.0295

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.0294

AC:

109

ESP6500EA

AF:

0.00694

AC:

ExAC

AF:

0.0271

AC:

3273

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00545

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alstrom syndrome (3)

not provided (2)

not specified (2)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.3

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.030

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

PhyloP100

-0.25

PrimateAI

Benign

0.41

Sift4G

Benign

0.50

Vest4

0.044

ClinPred

0.015

GERP RS

-0.87

Varity_R

0.033

gMVP

0.25

Mutation Taster

=75/25

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