chr2-73385958-AGCGGCG-A

Variant names:

• chr2-73385958-AGCGGCG-A
• rs746896173
• NM_001378454.1:c.100_105delGCGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM4 BP6

The NM_001378454.1(ALMS1):​c.100_105delGCGGCG​(p.Ala34_Ala35del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000801 in 1,248,122 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. A34A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.272
• 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001378454.1.
• BP6: Variant 2-73385958-AGCGGCG-A is Benign according to our data. Variant chr2-73385958-AGCGGCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 669342.

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.100_105delGCGGCG	p.Ala34_Ala35del	conservative_inframe_deletion	Exon 1 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.100_105delGCGGCG	p.Ala34_Ala35del	conservative_inframe_deletion	Exon 1 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.100_105delGCGGCG	p.Ala34_Ala35del	conservative_inframe_deletion	Exon 1 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.100_105delGCGGCG	p.Ala34_Ala35del	conservative_inframe_deletion	Exon 1 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000614410.4	TSL:5	c.100_105delGCGGCG	p.Ala34_Ala35del	conservative_inframe_deletion	Exon 1 of 16	ENSP00000479094.1	A0A087WV20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000144 AC: 2 AN: 139126 AF XY: 0.0000271

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000801 AC: 10 AN: 1248122 Hom.: 0 AF XY: 0.00000482 AC XY: 3 AN XY: 622358

African (AFR) AF: 0.00 AC: 0 AN: 28768

American (AMR) AF: 0.00 AC: 0 AN: 35042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23832

East Asian (EAS) AF: 0.00 AC: 0 AN: 34376

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5244

European-Non Finnish (NFE) AF: 0.00000953 AC: 9 AN: 944762

Other (OTH) AF: 0.00 AC: 0 AN: 52890

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000480 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Alstrom syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
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: rs746896173; hg19: chr2-73613086;