14-94563822-G-C

Position:

• chr14-94563822-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006215.4(SERPINA4):​c.340G>C​(p.Glu114Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA4 NM_006215.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.149

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38550347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA4	NM_006215.4	c.340G>C	p.Glu114Gln	missense_variant	2/5	ENST00000557004.6
SERPINA4	NM_001289032.2	c.451G>C	p.Glu151Gln	missense_variant	2/5
SERPINA4	NM_001289033.2	c.340G>C	p.Glu114Gln	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA4	ENST00000557004.6	c.340G>C	p.Glu114Gln	missense_variant	2/5	1	NM_006215.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Jan 23, 2024

The c.340G>C (p.E114Q) 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 340, causing the glutamic acid (E) at amino acid position 114 to be replaced by a glutamine (Q). 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	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.065	N
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.027	D;D;D
Sift4G	Benign	0.066	T;T;T
Polyphen		0.89	P;P;P
Vest4		0.084
MutPred		0.67		Gain of catalytic residue at L109 (P = 0.0032);Gain of catalytic residue at L109 (P = 0.0032);Gain of catalytic residue at L109 (P = 0.0032);
MVP		0.86
MPC		0.057
ClinPred		0.35	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.12

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95030159;