rs377354387

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001378454.1(ALMS1):c.4163C>T(p.Pro1388Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,744 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). Synonymous variant affecting the same amino acid position (i.e. P1388P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.182

Publications

1 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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07416454).

BP6

Variant 2-73450690-C-T is Benign according to our data. Variant chr2-73450690-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 393372.

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.4163C>T	p.Pro1388Leu	missense	Exon 8 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.4163C>T	p.Pro1388Leu	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.4163C>T	p.Pro1388Leu	missense	Exon 8 of 23	ENSP00000482968.1
ALMS1	ENST00000484298.5	TSL:1	c.4037C>T	p.Pro1346Leu	missense	Exon 7 of 22	ENSP00000478155.1
ALMS1	ENST00000684548.1		c.3782C>T	p.Pro1261Leu	missense	Exon 6 of 21	ENSP00000507421.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000281

AC:

AN:

249268

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33448

American (AMR)

AF:

0.0000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111730

Other (OTH)

AF:

0.0000166

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151224

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73788

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41044

American (AMR)

AF:

0.00

AC:

AN:

15124

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000847

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alstrom syndrome (3)

Cardiovascular phenotype (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.080

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.84

M_CAP

Benign

0.012

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

PhyloP100

0.18

PrimateAI

Benign

0.30

Sift4G

Uncertain

0.0030

Vest4

0.21

MVP

0.14

ClinPred

0.29

GERP RS

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.092

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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