1-231352778-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.149

Publications

49 publications found

Variant links:

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: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

SPRTN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRTN	NM_032018.7 link	c.887C>T	p.Pro296Leu	missense_variant	Exon 5 of 5	ENST00000295050.12	NP_114407.3	Q9H040-1A0A024R3U2
SPRTN	XM_006711818.4 link	c.758C>T	p.Pro253Leu	missense_variant	Exon 4 of 4		XP_006711881.1
SPRTN	NM_001010984.4 link	c.*1172C>T		3_prime_UTR_variant	Exon 4 of 4		NP_001010984.1	Q9H040-2
SPRTN	NM_001261462.3 link	c.*1172C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001248391.1	Q9H040-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPRTN	ENST00000295050.12 link	c.887C>T	p.Pro296Leu	missense_variant	Exon 5 of 5	1	NM_032018.7	ENSP00000295050.7	Q9H040-1
SPRTN	ENST00000391858.8 link	c.*1172C>T		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000375731.4	Q9H040-2
SPRTN	ENST00000366644.3 link	c.*14C>T		downstream_gene_variant		5		ENSP00000355604.3	B1AKT1
SPRTN	ENST00000469904.1 link	n.*24C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.577

AC:

87729

AN:

151960

Hom.:

25817

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.618

AC XY:

449183

AN XY:

727036

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

19907

39814

59722

79629

99536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18544

37088

55632

74176

92720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.577

AC:

87773

AN:

152080

Hom.:

25827

Cov.:

AF XY:

0.581

AC XY:

43160

AN XY:

74322

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1898

3796

5693

7591

9489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progeroid features-hepatocellular carcinoma predisposition syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

SPRTN-related disorder

Benign:1

Sep 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

6.7

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.022

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0000024

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.73

PhyloP100

0.15

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

REVEL

Benign

0.039

Sift

Benign

0.29

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.014

MPC

0.019

ClinPred

0.0071

GERP RS

1.3

Varity_R

0.019

gMVP

0.60

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over