ENST00000391858.8:c.718_721delGGTA

Variant names:

• chr1-231351569-AAGGT-A
• rs587593493
• ENST00000391858.8:c.718_721delGGTA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Moderate

The ENST00000391858.8(SPRTN):​c.718_721delGGTA​(p.Gly240ProfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRTN ENST00000391858.8 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.12

Genes affected

SPRTN (HGNC:25356): (SprT-like N-terminal domain) The protein encoded by this gene may play a role in DNA repair during replication of damaged DNA. This protein recruits valosin containing protein (p97) to stalled DNA replication forks where it may prevent excessive translesional DNA synthesis and limit the number of DNA-damage induced mutations. It may also be involved in replication-related G2/M-checkpoint regulation. Deficiency of a similar protein in mouse causes chromosomal instability and progeroid phenotypes. Mutations in this gene have been associated with Ruijs-Aalfs syndrome (RJALS). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0465 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-231351569-AAGGT-A is Pathogenic according to our data. Variant chr1-231351569-AAGGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 143915.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-231351569-AAGGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRTN	NM_032018.7	c.718_718+3delGGTA	p.Asp240AsnfsTer9	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 4 of 5	ENST00000295050.12	NP_114407.3
SPRTN	NM_001010984.4	c.718_721delGGTA	p.Gly240ProfsTer7	frameshift_variant	Exon 4 of 4		NP_001010984.1
SPRTN	NM_001261462.3	c.589_592delGGTA	p.Gly197ProfsTer7	frameshift_variant	Exon 3 of 3		NP_001248391.1
SPRTN	XM_006711818.4	c.589_589+3delGGTA	p.Asp197AsnfsTer9	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 4		XP_006711881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRTN	ENST00000295050.12	c.718_718+3delGGTA	p.Asp240AsnfsTer9	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 4 of 5	1	NM_032018.7	ENSP00000295050.7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

-

Neurogenetics Research; Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

-

Neurogenetics Research; Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Progeroid features-hepatocellular carcinoma predisposition syndrome Pathogenic:1

Nov 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587593493; hg19: chr1-231487315;