2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001378454.1(ALMS1):c.57_74delGGAGGAGGAGGAGGAGGA(p.Glu20_Glu25del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 701,364 control chromosomes in the GnomAD database, including 4 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E19del) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0014 ( 3 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: 3.45

Publications

7 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:

ENSG00000285068 (HGNC:):

ENSG00000285068 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-TGGAGGAGGAGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGAGGAGGAGGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1676370.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00114 (164/143636) while in subpopulation NFE AF = 0.00109 (70/64334). AF 95% confidence interval is 0.000883. There are 1 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-240_-223delTCCTCCTCCTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-240_-223delTCCTCCTCCTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.57_74delGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

164

AN:

143532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00862

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00135

AC:

754

AN:

557728

Hom.:

AF XY:

0.00131

AC XY:

391

AN XY:

297826

show subpopulations

African (AFR)

AF:

0.000570

AC:

AN:

15784

American (AMR)

AF:

0.000192

AC:

AN:

31236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17646

East Asian (EAS)

AF:

0.000130

AC:

AN:

30668

South Asian (SAS)

AF:

0.000107

AC:

AN:

55946

European-Finnish (FIN)

AF:

0.00870

AC:

316

AN:

36320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2422

European-Non Finnish (NFE)

AF:

0.00116

AC:

392

AN:

337586

Other (OTH)

AF:

0.000697

AC:

AN:

30120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

104

139

174

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:

0.00114

AC:

164

AN:

143636

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

AN XY:

69662

show subpopulations

African (AFR)

AF:

0.000300

AC:

AN:

39970

American (AMR)

AF:

0.0000680

AC:

AN:

14700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3322

East Asian (EAS)

AF:

0.00

AC:

AN:

4584

South Asian (SAS)

AF:

0.00

AC:

AN:

4264

European-Finnish (FIN)

AF:

0.00862

AC:

AN:

9398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

64334

Other (OTH)

AF:

0.00

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00259

Hom.:

1022

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 18, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 7 amino acids in a repetitive region with no known function; In silico analysis supports a deleterious effect on protein structure/function -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.4

Mutation Taster

=190/10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over