14-94563828-G-A

Variant names:

• chr14-94563828-G-A
• rs538199214
• NM_006215.4:c.346G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006215.4(SERPINA4):​c.346G>A​(p.Asp116Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D116Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SERPINA4 NM_006215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

Genes affected

SERPINA4 (HGNC:8948): (serpin family A member 4) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Located in extracellular exosome. Biomarker of diabetic retinopathy. [provided by Alliance of Genome Resources, Apr 2022]

SERPINA5 (HGNC:8723): (serpin family A member 5) The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. This family member is a glycoprotein that can inhibit several serine proteases, including protein C and various plasminogen activators and kallikreins, and it thus plays diverse roles in hemostasis and thrombosis in multiple organs. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA4	NM_006215.4	c.346G>A	p.Asp116Asn	missense_variant	Exon 2 of 5	ENST00000557004.6	NP_006206.2
SERPINA4	NM_001289032.2	c.457G>A	p.Asp153Asn	missense_variant	Exon 2 of 5		NP_001275961.1
SERPINA4	NM_001289033.2	c.346G>A	p.Asp116Asn	missense_variant	Exon 2 of 5		NP_001275962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA4	ENST00000557004.6	c.346G>A	p.Asp116Asn	missense_variant	Exon 2 of 5	1	NM_006215.4	ENSP00000450838.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251386 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727230

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346G>A (p.D116N) alteration is located in exon 2 (coding exon 1) of the SERPINA4 gene. This alteration results from a G to A substitution at nucleotide position 346, causing the aspartic acid (D) at amino acid position 116 to be replaced by an asparagine (N). 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	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	.;.;T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.15
MutPred		0.54		Gain of catalytic residue at E111 (P = 0.1295);Gain of catalytic residue at E111 (P = 0.1295);Gain of catalytic residue at E111 (P = 0.1295);
MVP		0.89
MPC		0.31
ClinPred		0.84	D
GERP RS		1.4
Varity_R		0.25
gMVP		0.15

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: rs538199214; hg19: chr14-95030165; COSMIC: COSV54068877;