14-94563901-G-C

Variant names:

• chr14-94563901-G-C
• rs758464001
• NM_006215.4:c.419G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G140S) has been classified 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
• Publications: 1 publications found

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]

ENSG00000294537 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA4	NM_006215.4	MANE Select	c.419G>C	p.Gly140Ala	missense	Exon 2 of 5	NP_006206.2
	SERPINA4	NM_001289032.2		c.530G>C	p.Gly177Ala	missense	Exon 2 of 5	NP_001275961.1
	SERPINA4	NM_001289033.2		c.419G>C	p.Gly140Ala	missense	Exon 2 of 5	NP_001275962.1	P29622

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA4	ENST00000557004.6	TSL:1 MANE Select	c.419G>C	p.Gly140Ala	missense	Exon 2 of 5	ENSP00000450838.1	P29622
	SERPINA4	ENST00000298841.5	TSL:1	c.419G>C	p.Gly140Ala	missense	Exon 2 of 5	ENSP00000298841.5	P29622
	SERPINA4	ENST00000555095.5	TSL:1	c.419G>C	p.Gly140Ala	missense	Exon 2 of 5	ENSP00000451172.1	P29622

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.90	L
PhyloP100		6.1
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.050	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.81		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
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs758464001; hg19: chr14-95030238;