14-94288287-T-C

Variant names:

• chr14-94288287-T-C
• rs1895072578
• NM_001100607.3:c.991A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001100607.3(SERPINA10):​c.991A>G​(p.Arg331Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SERPINA10 NM_001100607.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA10	NM_001100607.3	c.991A>G	p.Arg331Gly	missense_variant, splice_region_variant	Exon 3 of 5	ENST00000261994.9	NP_001094077.1
SERPINA10	NM_016186.3	c.991A>G	p.Arg331Gly	missense_variant, splice_region_variant	Exon 3 of 5		NP_057270.1
SERPINA10	XM_017021353.2	c.1111A>G	p.Arg371Gly	missense_variant, splice_region_variant	Exon 4 of 6		XP_016876842.1
SERPINA10	XM_005267733.6	c.991A>G	p.Arg331Gly	missense_variant, splice_region_variant	Exon 3 of 5		XP_005267790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA10	ENST00000261994.9	c.991A>G	p.Arg331Gly	missense_variant, splice_region_variant	Exon 3 of 5	1	NM_001100607.3	ENSP00000261994.4
SERPINA10	ENST00000554723.5	c.1111A>G	p.Arg371Gly	missense_variant, splice_region_variant	Exon 3 of 5	1		ENSP00000450896.1
SERPINA10	ENST00000393096.5	c.991A>G	p.Arg331Gly	missense_variant, splice_region_variant	Exon 3 of 5	1		ENSP00000376809.1
SERPINA10	ENST00000554173.1	c.991A>G	p.Arg331Gly	missense_variant, splice_region_variant	Exon 2 of 4	1		ENSP00000450971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461330 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.991A>G (p.R331G) alteration is located in exon 3 (coding exon 2) of the SERPINA10 gene. This alteration results from a A to G substitution at nucleotide position 991, causing the arginine (R) at amino acid position 331 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.76	.;T;T;.
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.5	M;.;M;M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.49
MutPred		0.70		Loss of MoRF binding (P = 0.0208);.;Loss of MoRF binding (P = 0.0208);Loss of MoRF binding (P = 0.0208);
MVP		0.91
MPC		0.21
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.67
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.060		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: rs1895072578; hg19: chr14-94754624;