7-93890612-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006528.4(TFPI2):c.67G>A(p.Asp23Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,492 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TFPI2 NM_006528.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.84

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029934615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFPI2	NM_006528.4	c.67G>A	p.Asp23Asn	missense_variant	1/5	ENST00000222543.11
TFPI2	NM_001271003.2	c.67G>A	p.Asp23Asn	missense_variant	1/5
TFPI2	NM_001271004.2	c.67G>A	p.Asp23Asn	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFPI2	ENST00000222543.11	c.67G>A	p.Asp23Asn	missense_variant	1/5	1	NM_006528.4	P2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 36 AN: 245564 Hom.: 0 AF XY: 0.000194 AC XY: 26 AN XY: 133894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000203 AC: 296 AN: 1461138 Hom.: 0 Cov.: 31 AF XY: 0.000220 AC XY: 160 AN XY: 726916

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74504

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000372 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000436

EpiControl AF: 0.000415

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 02, 2024

The c.67G>A (p.D23N) alteration is located in exon 1 (coding exon 1) of the TFPI2 gene. This alteration results from a G to A substitution at nucleotide position 67, causing the aspartic acid (D) at amino acid position 23 to be replaced by an asparagine (N). 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	0.087
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	5.6
Dann	Benign	0.96
DEOGEN2	Benign	0.072	T;T;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.034	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.030	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.020	N;.;.;.;.
REVEL	Benign	0.015
Sift	Benign	0.47	T;.;.;.;.
Sift4G	Benign	0.54	T;.;.;.;.
Polyphen		0.0060	B;B;.;.;.
Vest4		0.050
MVP		0.27
MPC		0.15
ClinPred		0.027	T
GERP RS		-6.3
Varity_R		0.061
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs149847293; hg19: chr7-93519924;