NM_001378454.1:c.54_74delGGAGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_001378454.1(ALMS1):c.54_74delGGAGGAGGAGGAGGAGGAGGA(p.Glu19_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 0.0000428 in 701,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E18E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-TGGAGGAGGAGGAGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGAGGAGGAGGAGGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 550448.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.54_74delGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.54_74delGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25del	disruptive_inframe_deletion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-243_-223delTCCTCCTCCTCCTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-243_-223delTCCTCCTCCTCCTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.54_74delGGAGGAGGAGGAGGAGGAGGA	p.Glu19_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0000418

AC:

AN:

143530

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000217

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000430

AC:

AN:

557736

Hom.:

AF XY:

0.0000504

AC XY:

AN XY:

297828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15796

American (AMR)

AF:

0.00

AC:

AN:

31236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17644

East Asian (EAS)

AF:

0.00

AC:

AN:

30670

South Asian (SAS)

AF:

0.0000715

AC:

AN:

55944

European-Finnish (FIN)

AF:

0.0000551

AC:

AN:

36320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2422

European-Non Finnish (NFE)

AF:

0.0000474

AC:

AN:

337584

Other (OTH)

AF:

0.0000664

AC:

AN:

30120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

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:

0.0000418

AC:

AN:

143634

Hom.:

Cov.:

AF XY:

0.0000574

AC XY:

AN XY:

69662

show subpopulations

African (AFR)

AF:

0.0000250

AC:

AN:

39968

American (AMR)

AF:

0.000204

AC:

AN:

14700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3322

East Asian (EAS)

AF:

0.000218

AC:

AN:

4584

South Asian (SAS)

AF:

0.00

AC:

AN:

4264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64334

Other (OTH)

AF:

0.00

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1022

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:3Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.4

Mutation Taster

=189/11

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over