chr14-94290332-G-A

Variant names:

• chr14-94290332-G-A
• rs2232698
• NM_001100607.3:c.262C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001100607.3(SERPINA10):​c.262C>T​(p.Arg88*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,614,230 control chromosomes in the GnomAD database, including 84 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (78 hom.)
• Consequence: SERPINA10 NM_001100607.3 stop_gained
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.99

Genes affected

SERPINA10 (HGNC:15996): (serpin family A member 10) The protein encoded by this gene belongs to the serpin family. It is predominantly expressed in the liver and secreted in plasma. It inhibits the activity of coagulation factors Xa and XIa in the presence of protein Z, calcium and phospholipid. Mutations in this gene are associated with venous thrombosis. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 14-94290332-G-A is Benign according to our data. Variant chr14-94290332-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 979156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA10	NM_001100607.3	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 5	ENST00000261994.9	NP_001094077.1
SERPINA10	NM_016186.3	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 5		NP_057270.1
SERPINA10	XM_017021353.2	c.382C>T	p.Arg128*	stop_gained	Exon 3 of 6		XP_016876842.1
SERPINA10	XM_005267733.6	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 5		XP_005267790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA10	ENST00000261994.9	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 5	1	NM_001100607.3	ENSP00000261994.4
SERPINA10	ENST00000554723.5	c.382C>T	p.Arg128*	stop_gained	Exon 2 of 5	1		ENSP00000450896.1
SERPINA10	ENST00000393096.5	c.262C>T	p.Arg88*	stop_gained	Exon 2 of 5	1		ENSP00000376809.1
SERPINA10	ENST00000554173.1	c.262C>T	p.Arg88*	stop_gained	Exon 1 of 4	1		ENSP00000450971.1

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 810 AN: 152228 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.00630

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00718 AC: 1802 AN: 251086 Hom.: 13 AF XY: 0.00797 AC XY: 1081 AN XY: 135716

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0156

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00665

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00657 AC: 9604 AN: 1461884 Hom.: 78 Cov.: 37 AF XY: 0.00702 AC XY: 5105 AN XY: 727242

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00686

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00565

Gnomad4 OTH exome AF: 0.00901

GnomAD4 genome AF: 0.00530 AC: 808 AN: 152346 Hom.: 6 Cov.: 33 AF XY: 0.00554 AC XY: 413 AN XY: 74494

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00764

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00744 Hom.: 27

Bravo AF: 0.00521

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00749 AC: 909

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00942

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

LAMB2-related infantile-onset nephrotic syndrome Benign:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg88Ter variant in SERPINA10 has been identified in 3 individuals with venous thromboembolic disease, including an individual with Factor V Leiden, and 1 homozygous individual with autism spectrum disorder (PMID: 15461625, 22039093, 23352160), and has been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). A meta-analysis suggests this variant does not cause increased risk of disease (PMID: 18710385). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant venous thromboembolic disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.77	D
Vest4		0.85
GERP RS		3.0

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

LitVar

Other links and lift over

dbSNP: rs2232698; hg19: chr14-94756669; COSMIC: COSV56229608;