rs201478438

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS1

The NM_001378454.1(ALMS1):c.759T>A(p.Pro253Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,604,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.83

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, 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-73422969-T-A is Benign according to our data. Variant chr2-73422969-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 391952.

BP7

Synonymous conserved (PhyloP=1.83 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000172 (25/1451830) while in subpopulation AFR AF = 0.000723 (24/33210). AF 95% confidence interval is 0.000498. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. 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.759T>A	p.Pro253Pro	synonymous	Exon 4 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.759T>A	p.Pro253Pro	synonymous	Exon 4 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.759T>A	p.Pro253Pro	synonymous	Exon 4 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.633T>A	p.Pro211Pro	synonymous	Exon 3 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000684548.1		c.309T>A	p.Pro103Pro	synonymous	Exon 2 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000562

AC:

AN:

249298

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.000840

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1451830

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722862

show subpopulations

African (AFR)

AF:

0.000723

AC:

AN:

33210

American (AMR)

AF:

0.0000224

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102978

Other (OTH)

AF:

0.00

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000184

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41570

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

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:

0.0000868

Hom.:

Bravo

AF:

0.000200

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alstrom syndrome (2)

Cardiovascular phenotype (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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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