dbSNP rs973057702: ALMS1:p.Ala31del (chr2-73385955-TGCA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PM4_SupportingBP6

The NM_001378454.1(ALMS1):c.90_92delAGC(p.Ala31del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,367,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A30A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.806

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001378454.1. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 2-73385955-TGCA-T is Benign according to our data. Variant chr2-73385955-TGCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 550960.

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.90_92delAGC	p.Ala31del	disruptive_inframe_deletion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.90_92delAGC	p.Ala31del	disruptive_inframe_deletion	Exon 1 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.90_92delAGC	p.Ala31del	disruptive_inframe_deletion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.90_92delAGC	p.Ala31del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000614410.4	TSL:5	c.90_92delAGC	p.Ala31del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes

AF:

0.00000674

AC:

AN:

148308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000210

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

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1219080

Hom.:

AF XY:

0.00

AC XY:

AN XY:

608932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28302

American (AMR)

AF:

0.00

AC:

AN:

34680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23512

East Asian (EAS)

AF:

0.000119

AC:

AN:

33728

South Asian (SAS)

AF:

0.00

AC:

AN:

73752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5092

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

919622

Other (OTH)

AF:

0.00

AC:

AN:

51888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

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:

0.00000674

AC:

AN:

148432

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40852

American (AMR)

AF:

0.00

AC:

AN:

14940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.000210

AC:

AN:

4756

South Asian (SAS)

AF:

0.00

AC:

AN:

4574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66612

Other (OTH)

AF:

0.00

AC:

AN:

2036

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.81

Mutation Taster

=87/13

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over