14-94563901-G-C

Position:

• chr14-94563901-G-C

Variant summary

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

The NM_006215.4(SERPINA4):​c.419G>C​(p.Gly140Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SERPINA4 NM_006215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA4	NM_006215.4	c.419G>C	p.Gly140Ala	missense_variant	2/5	ENST00000557004.6	NP_006206.2
SERPINA4	NM_001289032.2	c.530G>C	p.Gly177Ala	missense_variant	2/5		NP_001275961.1
SERPINA4	NM_001289033.2	c.419G>C	p.Gly140Ala	missense_variant	2/5		NP_001275962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA4	ENST00000557004.6	c.419G>C	p.Gly140Ala	missense_variant	2/5	1	NM_006215.4	ENSP00000450838	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2024

The c.419G>C (p.G140A) alteration is located in exon 2 (coding exon 1) of the SERPINA4 gene. This alteration results from a G to C substitution at nucleotide position 419, causing the glycine (G) at amino acid position 140 to be replaced by an alanine (A). 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	0.22
BayesDel_addAF	Benign	-0.0054	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	.;.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.050	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.56
MutPred		0.81		Gain of catalytic residue at L135 (P = 4e-04);Gain of catalytic residue at L135 (P = 4e-04);Gain of catalytic residue at L135 (P = 4e-04);
MVP		0.92
MPC		0.35
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.72
gMVP		0.68

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: rs758464001; hg19: chr14-95030238;