rs754175473

Variant names:

• chr2-73385937-GGAGGAA-G
• rs754175473
• NM_001378454.1:c.75_80delAGAGGA

Your query was ambiguous. Multiple possible variants found:

• chr2-73385937-GGAGGAA-G
• chr2-73385937-GGAGGAA-GGAGGAAGAGGAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_001378454.1(ALMS1):​c.75_80delAGAGGA​(p.Glu26_Glu27del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000999 in 1,000,582 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. E25E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.524
• Publications: 0 publications found

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

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385937-GGAGGAA-G is Benign according to our data. Variant chr2-73385937-GGAGGAA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402364.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.75_80delAGAGGA	p.Glu26_Glu27del	disruptive_inframe_deletion	Exon 1 of 23	NP_001365383.1
	ALMS1	NM_015120.4		c.75_80delAGAGGA	p.Glu26_Glu27del	disruptive_inframe_deletion	Exon 1 of 23	NP_055935.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.75_80delAGAGGA	p.Glu26_Glu27del	disruptive_inframe_deletion	Exon 1 of 23	ENSP00000482968.1
	ALMS1	ENST00000484298.5	TSL:1	c.75_80delAGAGGA	p.Glu26_Glu27del	disruptive_inframe_deletion	Exon 1 of 22	ENSP00000478155.1
	ALMS1	ENST00000614410.4	TSL:5	c.75_80delAGAGGA	p.Glu26_Glu27del	disruptive_inframe_deletion	Exon 1 of 16	ENSP00000479094.1

Frequencies

GnomAD3 genomes AF: 0.0000229 AC: 3 AN: 131260 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000731

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: 0.0000322

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000805 AC: 7 AN: 869322 Hom.: 0 AF XY: 0.00000901 AC XY: 4 AN XY: 444024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16878

American (AMR) AF: 0.0000325 AC: 1 AN: 30770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20064

East Asian (EAS) AF: 0.00 AC: 0 AN: 33064

South Asian (SAS) AF: 0.00 AC: 0 AN: 63912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3886

European-Non Finnish (NFE) AF: 0.00000813 AC: 5 AN: 614652

Other (OTH) AF: 0.0000249 AC: 1 AN: 40110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000876766), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000229 AC: 3 AN: 131260 Hom.: 0 Cov.: 28 AF XY: 0.0000469 AC XY: 3 AN XY: 64008

African (AFR) AF: 0.00 AC: 0 AN: 30512

American (AMR) AF: 0.0000731 AC: 1 AN: 13674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3232

East Asian (EAS) AF: 0.00 AC: 0 AN: 4820

South Asian (SAS) AF: 0.00 AC: 0 AN: 4412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000322 AC: 2 AN: 62146

Other (OTH) AF: 0.00 AC: 0 AN: 1824

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Alstrom syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52
Mutation Taster		=195/5	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754175473; hg19: chr2-73613065;