NM_001378454.1:c.10628C>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.10628C>G(p.Thr3543Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,648 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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. T3543T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0067 ( 3 hom., cov: 32)

Exomes 𝑓: 0.011 ( 111 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 1.63

Publications

17 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=0.008732915).

BP6

Variant 2-73572505-C-G is Benign according to our data. Variant chr2-73572505-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221028.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00667 (1015/152192) while in subpopulation NFE AF = 0.0105 (717/67972). AF 95% confidence interval is 0.00991. There are 3 homozygotes in GnomAd4. There are 441 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.10628C>G	p.Thr3543Ser	missense	Exon 16 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.10628C>G	p.Thr3543Ser	missense	Exon 16 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.10628C>G	p.Thr3543Ser	missense	Exon 16 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.10502C>G	p.Thr3501Ser	missense	Exon 15 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000423048.5	TSL:1	n.*1047C>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000399833.1	H7C1D9

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1017

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00721

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00664

AC:

1642

AN:

247312

AF XY:

0.00680

show subpopulations

Gnomad AFR exome

AF:

0.00260

Gnomad AMR exome

AF:

0.00355

Gnomad ASJ exome

AF:

0.00968

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00140

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00550

GnomAD4 exome

AF:

0.0114

AC:

16640

AN:

1461456

Hom.:

111

Cov.:

AF XY:

0.0110

AC XY:

8026

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33458

American (AMR)

AF:

0.00385

AC:

172

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00888

AC:

232

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00511

AC:

441

AN:

86222

European-Finnish (FIN)

AF:

0.00162

AC:

AN:

53238

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0135

AC:

15010

AN:

1111908

Other (OTH)

AF:

0.0103

AC:

624

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

893

1786

2679

3572

4465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.00667

AC:

1015

AN:

152192

Hom.:

Cov.:

AF XY:

0.00593

AC XY:

441

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41538

American (AMR)

AF:

0.00720

AC:

110

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00312

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

717

AN:

67972

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0112

Hom.:

Bravo

AF:

0.00717

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00321

AC:

ESP6500EA

AF:

0.0117

AC:

ExAC

AF:

0.00685

AC:

827

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.0113

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

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

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

Eigen

Benign

-0.066

Eigen_PC

Benign

-0.043

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0087

MetaSVM

Benign

-1.1

PhyloP100

1.6

PrimateAI

Benign

0.39

Sift4G

Benign

0.11

Vest4

0.31

MVP

0.22

ClinPred

0.014

GERP RS

3.6

Varity_R

0.075

gMVP

0.086

Mutation Taster

=98/2

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