7-93890650-G-C

Variant names:

• chr7-93890650-G-C
• rs745447348
• NM_006528.4:c.29C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006528.4(TFPI2):​c.29C>G​(p.Ser10Trp) 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 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. S10L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TFPI2 NM_006528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.287
• Publications: 1 publications found

Genes affected

TFPI2 (HGNC:11761): (tissue factor pathway inhibitor 2) This gene encodes a member of the Kunitz-type serine proteinase inhibitor family. The protein can inhibit a variety of serine proteases including factor VIIa/tissue factor, factor Xa, plasmin, trypsin, chymotryspin and plasma kallikrein. This gene has been identified as a tumor suppressor gene in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

GNGT1 (HGNC:4411): (G protein subunit gamma transducin 1) This gene encodes the gamma subunit of transducin, a guanine nucleotide-binding protein (G protein) that is found in rod outer segments. Transducin, also known as GMPase, mediates the activation of a cyclic GTP-specific (guanosine monophosphate) phosphodiesterase by rhodopsin. [provided by RefSeq, Jul 2016]

TFPI2-DT (HGNC:40581): (TFPI2 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06678587).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006528.4. 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
	TFPI2	NM_006528.4	MANE Select	c.29C>G	p.Ser10Trp	missense	Exon 1 of 5	NP_006519.1	P48307-1
	TFPI2	NM_001271003.2		c.29C>G	p.Ser10Trp	missense	Exon 1 of 5	NP_001257932.1	P48307-2
	TFPI2	NM_001271004.2		c.29C>G	p.Ser10Trp	missense	Exon 1 of 5	NP_001257933.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPI2	ENST00000222543.11	TSL:1 MANE Select	c.29C>G	p.Ser10Trp	missense	Exon 1 of 5	ENSP00000222543.5	P48307-1
	TFPI2	ENST00000650573.1		c.29C>G	p.Ser10Trp	missense	Exon 1 of 5	ENSP00000497131.1	A0A3B3IS67
	TFPI2	ENST00000898459.1		c.29C>G	p.Ser10Trp	missense	Exon 1 of 4	ENSP00000568518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 243672 AF XY: 0.0000150

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460924 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726824

African (AFR) AF: 0.0000599 AC: 2 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111762

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	0.087
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.29
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.056
Sift	Benign	0.20	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.54		Loss of disorder (P = 0.0388)
MVP		0.33
MPC		0.46
ClinPred		0.062	T
GERP RS		-1.4
PromoterAI		0.035	Neutral
Varity_R		0.080
gMVP		0.45
Mutation Taster		=94/6	polymorphism

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: rs745447348; hg19: chr7-93519962;