rs398122991

Variant names:

• chr2-73448315-A-AGAGGCTTT
• rs398122991
• NM_001378454.1:c.1791_1798dupGGCTTTGA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378454.1(ALMS1):​c.1791_1798dupGGCTTTGA​(p.Lys600ArgfsTer3) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALMS1 NM_001378454.1 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: -0.121
• Publications: 1 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

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-73448315-A-AGAGGCTTT is Pathogenic according to our data. Variant chr2-73448315-A-AGAGGCTTT is described in ClinVar as Pathogenic. ClinVar VariationId is 92190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1791_1798dupGGCTTTGA	p.Lys600ArgfsTer3	frameshift stop_gained	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.1791_1798dupGGCTTTGA	p.Lys600ArgfsTer3	frameshift stop_gained	Exon 8 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.1791_1798dupGGCTTTGA	p.Lys600ArgfsTer3	frameshift stop_gained	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.1665_1672dupGGCTTTGA	p.Lys558ArgfsTer3	frameshift stop_gained	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.1410_1417dupGGCTTTGA	p.Lys473ArgfsTer3	frameshift stop_gained	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs398122991; hg19: chr2-73675442;