Genetic Variant TCAF1:p.Glu22Lys (chr7-143876545-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014719.3(TCAF1):c.64G>A(p.Glu22Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000842 in 1,543,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. E22Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

TCAF1
NM_014719.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

Variant links:

Genes affected

TCAF1 (HGNC:22201): (TRPM8 channel associated factor 1) Enables transmembrane transporter binding activity. Involved in negative regulation of cell migration; positive regulation of anion channel activity; and positive regulation of protein targeting to membrane. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TCAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.044889927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAF1	NM_014719.3 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 9	ENST00000479870.6	NP_055534.2	Q9Y4C2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCAF1	ENST00000479870.6 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 9	1	NM_014719.3	ENSP00000419235.1		Q9Y4C2-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000213

AC:

AN:

188112

Hom.:

AF XY:

0.0000101

AC XY:

AN XY:

98850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000122

Gnomad SAS exome

AF:

0.0000617

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.00000863

AC:

AN:

1391246

Hom.:

Cov.:

AF XY:

0.00000875

AC XY:

AN XY:

685714

show subpopulations

Gnomad4 AFR exome

AF:

0.0000322

Gnomad4 AMR exome

AF:

0.0000302

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.0000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000370

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0027

T;.;T;.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.33

T;T;.;T;T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.045

T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

0.060

N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.95

T;T;T;T;T;T

Sift4G

Benign

0.49

T;T;T;T;.;T

Polyphen

0.0010

B;.;.;.;.;.

Vest4

0.37

MutPred

0.39

Gain of methylation at E22 (P = 0.0188);Gain of methylation at E22 (P = 0.0188);Gain of methylation at E22 (P = 0.0188);Gain of methylation at E22 (P = 0.0188);Gain of methylation at E22 (P = 0.0188);Gain of methylation at E22 (P = 0.0188);

MVP

0.030

MPC

0.055

ClinPred

0.075

GERP RS

4.0

Varity_R

0.091

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over