NM_001378454.1:c.4222G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001378454.1(ALMS1):c.4222G>A(p.Val1408Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,612,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V1408F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: -0.959

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024667293).

BP6

Variant 2-73450749-G-A is Benign according to our data. Variant chr2-73450749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459867.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000398 (60/150690) while in subpopulation NFE AF = 0.000708 (48/67842). AF 95% confidence interval is 0.000548. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4222G>A	p.Val1408Ile	missense	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.4222G>A	p.Val1408Ile	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.4222G>A	p.Val1408Ile	missense	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.4096G>A	p.Val1366Ile	missense	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000684548.1		c.3841G>A	p.Val1281Ile	missense	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes

AF:

0.000398

AC:

AN:

150690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000199

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000967

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000708

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000409

AC:

102

AN:

249300

AF XY:

0.000340

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000560

AC:

818

AN:

1461436

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

400

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33442

American (AMR)

AF:

0.000492

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000151

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000664

AC:

738

AN:

1111672

Other (OTH)

AF:

0.000613

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000398

AC:

AN:

150690

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

AN XY:

73532

show subpopulations

African (AFR)

AF:

0.000196

AC:

AN:

40746

American (AMR)

AF:

0.000199

AC:

AN:

15068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

10346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000708

AC:

AN:

67842

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000509

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000607

AC:

ExAC

AF:

0.000430

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alstrom syndrome (3)

not specified (2)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.41

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.013

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.62

M_CAP

Benign

0.0029

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.0

PhyloP100

-0.96

PrimateAI

Benign

0.27

Sift4G

Benign

0.31

Vest4

0.043

MVP

0.22

ClinPred

0.0053

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.012

gMVP

0.016

Mutation Taster

=89/11

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