NM_001378454.1:c.5786G>A

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.5786G>A(p.Arg1929Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,848 control chromosomes in the GnomAD database, including 920 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1929W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.022 ( 125 hom., cov: 32)

Exomes 𝑓: 0.013 ( 795 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.06

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014262199).

BP6

Variant 2-73452313-G-A is Benign according to our data. Variant chr2-73452313-G-A is described in ClinVar as Benign. ClinVar VariationId is 389387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0836 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.5786G>A	p.Arg1929Gln	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.5786G>A	p.Arg1929Gln	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.5786G>A	p.Arg1929Gln	missense	Exon 8 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.5660G>A	p.Arg1887Gln	missense	Exon 7 of 22	ENSP00000478155.1
ALMS1	ENST00000423048.5	TSL:1	n.617G>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3359

AN:

151936

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0308

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0870

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00290

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00649

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.0321

AC:

7996

AN:

249024

AF XY:

0.0250

show subpopulations

Gnomad AFR exome

AF:

0.0337

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.00633

Gnomad OTH exome

AF:

0.0247

GnomAD4 exome

AF:

0.0128

AC:

18754

AN:

1461794

Hom.:

795

Cov.:

AF XY:

0.0118

AC XY:

8616

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.0301

AC:

1008

AN:

33476

American (AMR)

AF:

0.166

AC:

7411

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26132

East Asian (EAS)

AF:

0.00806

AC:

320

AN:

39698

South Asian (SAS)

AF:

0.00361

AC:

311

AN:

86256

European-Finnish (FIN)

AF:

0.0184

AC:

983

AN:

53402

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00710

AC:

7894

AN:

1111966

Other (OTH)

AF:

0.0121

AC:

732

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1180

2359

3539

4718

5898

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

424

848

1272

1696

2120

<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:

0.0222

AC:

3374

AN:

152054

Hom.:

125

Cov.:

AF XY:

0.0236

AC XY:

1755

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0309

AC:

1281

AN:

41462

American (AMR)

AF:

0.0875

AC:

1337

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00291

AC:

AN:

5154

South Asian (SAS)

AF:

0.00518

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00649

AC:

441

AN:

67972

Other (OTH)

AF:

0.0171

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

168

336

504

672

840

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:

0.0127

Hom.:

138

Bravo

AF:

0.0295

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.0292

AC:

110

ESP6500EA

AF:

0.00707

AC:

ExAC

AF:

0.0269

AC:

3251

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00736

EpiControl

AF:

0.00551

ClinVar

ClinVar submissions as Germline

Significance: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

0.057

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.6

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.015

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00026

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0014

MetaSVM

Benign

-0.95

PhyloP100

2.1

PrimateAI

Benign

0.22

Sift4G

Benign

1.0

Vest4

0.12

ClinPred

0.0011

GERP RS

2.0

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.039

gMVP

0.019

Mutation Taster

=100/0

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