rs587593493

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_032018.7(SPRTN):​c.718_718+3delGGTA​(p.Asp240AsnfsTer9) variant causes a frameshift, splice donor, splice region, intron 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 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.12
• Publications: 1 publications found

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]

SPRTN Gene-Disease associations (from GenCC):

• progeroid features-hepatocellular carcinoma predisposition syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.512 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-231351569-AAGGT-A is Pathogenic according to our data. Variant chr1-231351569-AAGGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 143915.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032018.7. 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
	SPRTN	NM_032018.7	MANE Select	c.718_718+3delGGTA	p.Asp240AsnfsTer9	frameshift splice_donor splice_region intron	Exon 4 of 5	NP_114407.3
	SPRTN	NM_001010984.4		c.718_721delGGTA	p.Gly240ProfsTer7	frameshift	Exon 4 of 4	NP_001010984.1	Q9H040-2
	SPRTN	NM_001261462.3		c.589_592delGGTA	p.Gly197ProfsTer7	frameshift	Exon 3 of 3	NP_001248391.1	Q9H040-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRTN	ENST00000391858.8	TSL:1	c.718_721delGGTA	p.Gly240ProfsTer7	frameshift	Exon 4 of 4	ENSP00000375731.4	Q9H040-2
	SPRTN	ENST00000295050.12	TSL:1 MANE Select	c.718_718+3delGGTA	p.Asp240AsnfsTer9	frameshift splice_donor splice_region intron	Exon 4 of 5	ENSP00000295050.7	Q9H040-1
	SPRTN	ENST00000008440.9	TSL:2	c.589_592delGGTA	p.Gly197ProfsTer7	frameshift	Exon 3 of 3	ENSP00000008440.9	Q9H040-3

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Progeroid features-hepatocellular carcinoma predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587593493; hg19: chr1-231487315;