rs587593493

chr1-231351569-AAGGT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Strong PM2 PP3_Moderate PP5_Moderate

The NM_032018.7(SPRTN):c.718_718+3del variant causes a splice donor, coding sequence change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPRTN NM_032018.7 splice_donor, coding_sequence
• 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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates 0.5122448979591836 fraction of the gene. No cryptic splice site detected. Exon removal results in frameshift change.
• 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/exons	MANE	UniProt
SPRTN	NM_032018.7	c.718_718+3del		splice_donor_variant, coding_sequence_variant	4/5	ENST00000295050.12
SPRTN	NM_001010984.4	c.718_721del	p.Gly240ProfsTer7	frameshift_variant	4/4
SPRTN	NM_001261462.3	c.589_592del	p.Gly197ProfsTer7	frameshift_variant	3/3
SPRTN	XM_006711818.4	c.589_589+3del		splice_donor_variant, coding_sequence_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRTN	ENST00000295050.12	c.718_718+3del		splice_donor_variant, coding_sequence_variant	4/5	1	NM_032018.7	P1

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

Pathogenic, flagged submission	literature only	Neurogenetics Research; Murdoch Childrens Research Institute	-	- -
Pathogenic, criteria provided, single submitter	literature only	Neurogenetics Research; Murdoch Childrens Research Institute	-	- -

Progeroid features-hepatocellular carcinoma predisposition syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2014

- -

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;