14-94489622-C-G

Variant names:

• chr14-94489622-C-G
• rs1445117727
• NM_001382267.1:c.1051G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382267.1(SERPINA12):​c.1051G>C​(p.Glu351Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E351V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SERPINA12 NM_001382267.1 missense, splice_region
• Scores: Splicing: ADA: 0.00001732
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.802
• Publications: 0 publications found

Genes affected

SERPINA12 (HGNC:18359): (serpin family A member 12) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to act upstream of or within negative regulation of gluconeogenesis; positive regulation of signal transduction; and regulation of lipid metabolic process. Predicted to be located in plasma membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINA12 Gene-Disease associations (from GenCC):

• hereditary palmoplantar keratoderma, Gamborg-Nielsen type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09129822).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382267.1. 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
	SERPINA12	NM_001382267.1	MANE Select	c.1051G>C	p.Glu351Gln	missense splice_region	Exon 4 of 5	NP_001369196.1	Q8IW75
	SERPINA12	NM_001304461.2		c.1051G>C	p.Glu351Gln	missense splice_region	Exon 4 of 5	NP_001291390.1	Q8IW75
	SERPINA12	NM_173850.4		c.1051G>C	p.Glu351Gln	missense splice_region	Exon 5 of 6	NP_776249.1	Q8IW75

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA12	ENST00000677451.1	MANE Select	c.1051G>C	p.Glu351Gln	missense splice_region	Exon 4 of 5	ENSP00000503935.1	Q8IW75
	SERPINA12	ENST00000341228.2	TSL:1	c.1051G>C	p.Glu351Gln	missense splice_region	Exon 5 of 6	ENSP00000342109.2	Q8IW75
	SERPINA12	ENST00000556881.5	TSL:1	c.1051G>C	p.Glu351Gln	missense splice_region	Exon 4 of 5	ENSP00000451738.1	Q8IW75

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.4
DANN	Benign	0.78
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.80
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.17
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.074	B
Vest4		0.18
MutPred		0.54		Gain of MoRF binding (P = 0.0225)
MVP		0.18
MPC		0.030
ClinPred		0.085	T
GERP RS		-0.43
Varity_R		0.17
gMVP		0.41
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0020
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: rs1445117727; hg19: chr14-94955959;