1-231352778-C-T

Variant names:

• chr1-231352778-C-T
• rs2437150
• NM_032018.7:c.887C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032018.7(SPRTN):​c.887C>T​(p.Pro296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,613,562 control chromosomes in the GnomAD database, including 307,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25827 hom., cov: 32)
  • Exomes 𝑓: 0.62 (281869 hom.)
• Consequence: SPRTN NM_032018.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.149
• Publications: 49 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.410465E-6).
• BP6: Variant 1-231352778-C-T is Benign according to our data. Variant chr1-231352778-C-T is described in ClinVar as Benign. ClinVar VariationId is 1333158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

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.887C>T	p.Pro296Leu	missense	Exon 5 of 5	NP_114407.3
	SPRTN	NM_001010984.4		c.*1172C>T		3_prime_UTR	Exon 4 of 4	NP_001010984.1	Q9H040-2
	SPRTN	NM_001261462.3		c.*1172C>T		3_prime_UTR	Exon 3 of 3	NP_001248391.1	Q9H040-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRTN	ENST00000295050.12	TSL:1 MANE Select	c.887C>T	p.Pro296Leu	missense	Exon 5 of 5	ENSP00000295050.7	Q9H040-1
	SPRTN	ENST00000391858.8	TSL:1	c.*1172C>T		3_prime_UTR	Exon 4 of 4	ENSP00000375731.4	Q9H040-2
	SPRTN	ENST00000885390.1		c.758C>T	p.Pro253Leu	missense	Exon 4 of 4	ENSP00000555449.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87729 AN: 151960 Hom.: 25817 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.591

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.637

Gnomad NFE AF: 0.641

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.597 AC: 149561 AN: 250474 AF XY: 0.601

Gnomad AFR exome AF: 0.451

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.574

Gnomad FIN exome AF: 0.689

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.619 AC: 904266 AN: 1461482 Hom.: 281869 Cov.: 58 AF XY: 0.618 AC XY: 449183 AN XY: 727036

African (AFR) AF: 0.444 AC: 14869 AN: 33458

American (AMR) AF: 0.513 AC: 22926 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 15288 AN: 26110

East Asian (EAS) AF: 0.557 AC: 22113 AN: 39684

South Asian (SAS) AF: 0.561 AC: 48320 AN: 86200

European-Finnish (FIN) AF: 0.689 AC: 36778 AN: 53386

Middle Eastern (MID) AF: 0.665 AC: 3837 AN: 5768

European-Non Finnish (NFE) AF: 0.633 AC: 703755 AN: 1111846

Other (OTH) AF: 0.603 AC: 36380 AN: 60362

GnomAD4 genome AF: 0.577 AC: 87773 AN: 152080 Hom.: 25827 Cov.: 32 AF XY: 0.581 AC XY: 43160 AN XY: 74322

African (AFR) AF: 0.452 AC: 18753 AN: 41452

American (AMR) AF: 0.550 AC: 8411 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 2051 AN: 3472

East Asian (EAS) AF: 0.553 AC: 2863 AN: 5178

South Asian (SAS) AF: 0.559 AC: 2696 AN: 4820

European-Finnish (FIN) AF: 0.700 AC: 7403 AN: 10580

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.641 AC: 43579 AN: 67982

Other (OTH) AF: 0.591 AC: 1248 AN: 2110

Alfa AF: 0.610 Hom.: 78043

Bravo AF: 0.561

TwinsUK AF: 0.646 AC: 2395

ALSPAC AF: 0.638 AC: 2458

ESP6500AA AF: 0.468 AC: 2061

ESP6500EA AF: 0.636 AC: 5473

ExAC AF: 0.598 AC: 72619

Asia WGS AF: 0.558 AC: 1939 AN: 3478

EpiCase AF: 0.637

EpiControl AF: 0.629

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.7
DANN	Benign	0.27
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0000024	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.73	N
PhyloP100		0.15
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.039
Sift	Benign	0.29	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.019
ClinPred		0.0071	T
GERP RS		1.3
Varity_R		0.019
gMVP		0.60
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2437150; hg19: chr1-231488524; COSMIC: COSV50478309; COSMIC: COSV50478309;