NM_001378454.1:c.1453A>G

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.1453A>G(p.Ile485Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,516 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I485I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:12

Conservation

PhyloP100: 0.408

Publications

6 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=0.004206747).

BP6

Variant 2-73447980-A-G is Benign according to our data. Variant chr2-73447980-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198873.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00185 (282/152282) while in subpopulation AMR AF = 0.00491 (75/15286). AF 95% confidence interval is 0.00401. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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.1453A>G	p.Ile485Val	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.1453A>G	p.Ile485Val	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.1453A>G	p.Ile485Val	missense	Exon 8 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.1327A>G	p.Ile443Val	missense	Exon 7 of 22	ENSP00000478155.1
ALMS1	ENST00000684548.1		c.1072A>G	p.Ile358Val	missense	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00172

AC:

428

AN:

248254

AF XY:

0.00174

show subpopulations

Gnomad AFR exome

AF:

0.000711

Gnomad AMR exome

AF:

0.00259

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00177

Gnomad NFE exome

AF:

0.00242

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00172

AC:

2508

AN:

1460234

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1219

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

33378

American (AMR)

AF:

0.00314

AC:

140

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000163

AC:

AN:

85926

European-Finnish (FIN)

AF:

0.00129

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00244

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00195

AC:

2171

AN:

1111170

Other (OTH)

AF:

0.00138

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

123

246

369

492

615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00185

AC:

282

AN:

152282

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41572

American (AMR)

AF:

0.00491

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00219

AC:

149

AN:

68010

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00216

Hom.:

Bravo

AF:

0.00219

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000535

AC:

ESP6500EA

AF:

0.00232

AC:

ExAC

AF:

0.00160

AC:

193

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00197

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Alstrom syndrome (4)

not specified (3)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.020

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.59

M_CAP

Benign

0.014

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

PhyloP100

0.41

PrimateAI

Benign

0.24

Sift4G

Benign

0.86

Polyphen

0.10

Vest4

0.051

MVP

0.17

ClinPred

0.0031

GERP RS

1.4

Varity_R

0.025

gMVP

0.019

Mutation Taster

=100/0

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over