Genetic Variant ALMS1:p.Ala35dup (chr2-73385958-A-AGCG) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_001378454.1(ALMS1):c.103_105dupGCG(p.Ala35dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,399,048 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. N36N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 0.260

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 1 ACMG points.

PM4

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

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.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	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.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
ALMS1	ENST00000484298.5	TSL:1	c.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
ALMS1	ENST00000614410.4	TSL:5	c.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

150814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000594

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000592

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000144

AC:

AN:

139126

AF XY:

0.000122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000475

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000102

Gnomad FIN exome

AF:

0.000276

Gnomad NFE exome

AF:

0.0000753

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

146

AN:

1248124

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

622360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28768

American (AMR)

AF:

0.000428

AC:

AN:

35042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23832

East Asian (EAS)

AF:

0.0000291

AC:

AN:

34376

South Asian (SAS)

AF:

0.00

AC:

AN:

74610

European-Finnish (FIN)

AF:

0.000144

AC:

AN:

48598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5244

European-Non Finnish (NFE)

AF:

0.000122

AC:

115

AN:

944764

Other (OTH)

AF:

0.000151

AC:

AN:

52890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000119

AC:

AN:

150924

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

73692

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41298

American (AMR)

AF:

0.000593

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.000202

AC:

AN:

4956

South Asian (SAS)

AF:

0.00

AC:

AN:

4740

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000592

AC:

AN:

67560

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alstrom syndrome (4)

ALMS1-related disorder (1)

Cardiovascular phenotype (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.26

Mutation Taster

=83/17

polymorphism

(source)

Splicing

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