2-73599494-C-T

Variant names:

Variant summary

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

The NM_001378454.1(ALMS1):c.11641C>T(p.His3881Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,580 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3881D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:10

Conservation

PhyloP100: 2.02

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01774621).

BP6

Variant 2-73599494-C-T is Benign according to our data. Variant chr2-73599494-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240979.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00103 (157/152274) while in subpopulation NFE AF = 0.00181 (123/68018). AF 95% confidence interval is 0.00155. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.11641C>T	p.His3881Tyr	missense	Exon 17 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.11641C>T	p.His3881Tyr	missense	Exon 17 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.11641C>T	p.His3881Tyr	missense	Exon 17 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.11515C>T	p.His3839Tyr	missense	Exon 16 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000684548.1		c.11260C>T	p.His3754Tyr	missense	Exon 15 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000964

AC:

240

AN:

248972

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000280

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.00172

AC:

2512

AN:

1461306

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1232

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33460

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000870

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.000413

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00211

AC:

2348

AN:

1111662

Other (OTH)

AF:

0.000878

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

120

239

359

478

598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.00103

AC:

157

AN:

152274

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41554

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00181

AC:

123

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000835

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000271

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00104

AC:

126

EpiCase

AF:

0.00202

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (4)

Alstrom syndrome (2)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.034

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.70

M_CAP

Benign

0.0026

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.0

PhyloP100

2.0

PrimateAI

Benign

0.34

Sift4G

Uncertain

0.013

Vest4

0.28

MVP

0.23

ClinPred

0.0060

GERP RS

3.9

Varity_R

0.065

gMVP

0.097

Mutation Taster

=92/8

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

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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