Genetic Variant NM_014719.3:c.64G>A (chr7-143876545-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -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. 14/20 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

Publications

11 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.044889927).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014719.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCAF1	NM_014719.3	MANE Select	c.64G>A	p.Glu22Lys	missense	Exon 2 of 9	NP_055534.2	Q9Y4C2-1
TCAF1	NM_001206938.2		c.64G>A	p.Glu22Lys	missense	Exon 2 of 9	NP_001193867.2	Q9Y4C2-2
TCAF1	NM_001206941.2		c.-653+8665G>A		intron	N/A	NP_001193870.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCAF1	ENST00000479870.6	TSL:1 MANE Select	c.64G>A	p.Glu22Lys	missense	Exon 2 of 9	ENSP00000419235.1	Q9Y4C2-1
TCAF1	ENST00000355951.2	TSL:1	c.64G>A	p.Glu22Lys	missense	Exon 2 of 9	ENSP00000348220.2	Q9Y4C2-2
TCAF1	ENST00000872784.1		c.64G>A	p.Glu22Lys	missense	Exon 2 of 9	ENSP00000542843.1

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

GnomAD2 exomes

AF:

0.0000213

AC:

AN:

188112

AF XY:

0.0000101

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 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

African (AFR)

AF:

0.0000322

AC:

AN:

31046

American (AMR)

AF:

0.0000302

AC:

AN:

33142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21000

East Asian (EAS)

AF:

0.000102

AC:

AN:

39374

South Asian (SAS)

AF:

0.0000278

AC:

AN:

71864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1081746

Other (OTH)

AF:

0.00

AC:

AN:

57226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0027

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.33

M_CAP

Benign

0.0020

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.1

PhyloP100

2.0

PrimateAI

Benign

0.43

PROVEAN

Benign

0.060

REVEL

Benign

0.15

Sift

Benign

0.95

Sift4G

Benign

0.49

Polyphen

0.0010

Vest4

0.37

MutPred

0.39

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

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over