2-73451886-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.5359A>G(p.Asn1787Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,611,588 control chromosomes in the GnomAD database, including 259 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1787K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 27 hom., cov: 32)

Exomes 𝑓: 0.015 ( 232 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -3.59

Publications

11 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=0.002682358).

BP6

Variant 2-73451886-A-G is Benign according to our data. Variant chr2-73451886-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0145 (2173/149794) while in subpopulation SAS AF = 0.0191 (89/4668). AF 95% confidence interval is 0.0172. There are 27 homozygotes in GnomAd4. There are 1136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 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.5359A>G	p.Asn1787Asp	missense	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.5359A>G	p.Asn1787Asp	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.5359A>G	p.Asn1787Asp	missense	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.5233A>G	p.Asn1745Asp	missense	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000423048.5	TSL:1	n.190A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2173

AN:

149672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00283

Gnomad AMI

AF:

0.0410

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0175

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0117

GnomAD2 exomes

AF:

0.0147

AC:

3665

AN:

248994

AF XY:

0.0157

show subpopulations

Gnomad AFR exome

AF:

0.00247

Gnomad AMR exome

AF:

0.00675

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0155

AC:

22642

AN:

1461794

Hom.:

232

Cov.:

AF XY:

0.0158

AC XY:

11486

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00251

AC:

AN:

33470

American (AMR)

AF:

0.00693

AC:

310

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

474

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0158

AC:

1360

AN:

86254

European-Finnish (FIN)

AF:

0.0352

AC:

1882

AN:

53418

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0159

AC:

17641

AN:

1111950

Other (OTH)

AF:

0.0134

AC:

812

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1557

3113

4670

6226

7783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.0145

AC:

2173

AN:

149794

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1136

AN XY:

73250

show subpopulations

African (AFR)

AF:

0.00282

AC:

115

AN:

40728

American (AMR)

AF:

0.0147

AC:

223

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3428

East Asian (EAS)

AF:

0.000204

AC:

AN:

4912

South Asian (SAS)

AF:

0.0191

AC:

AN:

4668

European-Finnish (FIN)

AF:

0.0386

AC:

405

AN:

10492

Middle Eastern (MID)

AF:

0.0150

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0180

AC:

1209

AN:

67186

Other (OTH)

AF:

0.0116

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

237

355

474

592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0151

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00243

AC:

ESP6500EA

AF:

0.0163

AC:

134

ExAC

AF:

0.0144

AC:

1738

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0175

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Alstrom syndrome (3)

not provided (3)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.011

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.0027

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PhyloP100

-3.6

PrimateAI

Benign

0.22

Sift4G

Benign

0.32

Vest4

0.044

ClinPred

0.0011

GERP RS

-9.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.028

Mutation Taster

=99/1

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