chr7-93889100-C-T

Position:

• chr7-93889100-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_006528.4(TFPI2):​c.395G>A​(p.Arg132Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,612,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TFPI2 NM_006528.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008853614).
• BP6: Variant 7-93889100-C-T is Benign according to our data. Variant chr7-93889100-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 730260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPI2	NM_006528.4	c.395G>A	p.Arg132Gln	missense_variant	3/5	ENST00000222543.11	NP_006519.1
TFPI2	NM_001271003.2	c.362G>A	p.Arg121Gln	missense_variant	3/5		NP_001257932.1
TFPI2	NM_001271004.2	c.395G>A	p.Arg132Gln	missense_variant	3/5		NP_001257933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPI2	ENST00000222543.11	c.395G>A	p.Arg132Gln	missense_variant	3/5	1	NM_006528.4	ENSP00000222543.5

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000381 AC: 95 AN: 249562 Hom.: 0 AF XY: 0.000259 AC XY: 35 AN XY: 134954

Gnomad AFR exome AF: 0.00527

Gnomad AMR exome AF: 0.000237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1460486 Hom.: 0 Cov.: 31 AF XY: 0.000160 AC XY: 116 AN XY: 726526

Gnomad4 AFR exome AF: 0.00578

Gnomad4 AMR exome AF: 0.000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74408

Gnomad4 AFR AF: 0.00537

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.00193

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.3
DANN	Benign	0.84
DEOGEN2	Benign	0.047	T;T;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.46	.;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0089	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	N;N;.;.;.;.
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.15	N;.;N;.;.;.
REVEL	Benign	0.018
Sift	Benign	0.32	T;.;T;.;.;.
Sift4G	Benign	0.14	T;.;T;.;.;.
Polyphen		0.073	B;B;.;.;.;.
Vest4		0.12
MVP		0.26
MPC		0.15
ClinPred		0.0018	T
GERP RS		-3.7
Varity_R		0.020
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs113538343; hg19: chr7-93518412; COSMIC: COSV55990504; COSMIC: COSV55990504;