7-93890265-A-C

Variant names:

• chr7-93890265-A-C
• rs1369212220
• NM_006528.4:c.143T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006528.4(TFPI2):​c.143T>G​(p.Leu48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,360 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TFPI2 NM_006528.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.10

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09212211).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPI2	NM_006528.4	c.143T>G	p.Leu48Arg	missense_variant	Exon 2 of 5	ENST00000222543.11	NP_006519.1
TFPI2	NM_001271003.2	c.110T>G	p.Leu37Arg	missense_variant	Exon 2 of 5		NP_001257932.1
TFPI2	NM_001271004.2	c.143T>G	p.Leu48Arg	missense_variant	Exon 2 of 5		NP_001257933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPI2	ENST00000222543.11	c.143T>G	p.Leu48Arg	missense_variant	Exon 2 of 5	1	NM_006528.4	ENSP00000222543.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251050 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461360 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 11, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.45
DANN	Benign	0.46
DEOGEN2	Benign	0.061	T;T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.028	N
LIST_S2	Uncertain	0.92	.;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.092	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;.;.;.;.
REVEL	Benign	0.098
Sift	Benign	0.49	T;.;.;.;.
Sift4G	Benign	0.45	T;.;.;.;.
Polyphen		0.0020	B;B;.;.;.
Vest4		0.19
MutPred		0.51		Gain of methylation at L48 (P = 0.0135);Gain of methylation at L48 (P = 0.0135);Gain of methylation at L48 (P = 0.0135);.;Gain of methylation at L48 (P = 0.0135);
MVP		0.19
MPC		0.19
ClinPred		0.038	T
GERP RS		-9.8
Varity_R		0.41
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1369212220; hg19: chr7-93519577;