Genetic Variant NM_007284.4:c.411C>T (chr3-52231199-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BS1BS2

The NM_007284.4(TWF2):c.411C>T(p.His137His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,614,020 control chromosomes in the GnomAD database, including 1,792 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.035 ( 138 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1654 hom. )

Consequence

TWF2
NM_007284.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.310

Publications

19 publications found

Variant links:

Genes affected

TWF2 (HGNC:9621): (twinfilin actin binding protein 2) The protein encoded by this gene was identified by its interaction with the catalytic domain of protein kinase C-zeta. The encoded protein contains an actin-binding site and an ATP-binding site. It is most closely related to twinfilin (PTK9), a conserved actin monomer-binding protein. [provided by RefSeq, Jul 2008]

TWF2 links:

ENSG00000173366 (HGNC:):

ENSG00000173366 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP7

Synonymous conserved (PhyloP=0.31 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0351 (5336/152208) while in subpopulation NFE AF = 0.0492 (3345/67982). AF 95% confidence interval is 0.0478. There are 138 homozygotes in GnomAd4. There are 2471 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 5336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWF2	NM_007284.4 link	c.411C>T	p.His137His	synonymous_variant	Exon 5 of 9	ENST00000305533.10	NP_009215.1	Q6IBS0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWF2	ENST00000305533.10 link	c.411C>T	p.His137His	synonymous_variant	Exon 5 of 9	1	NM_007284.4	ENSP00000303908.4		Q6IBS0
ENSG00000173366	ENST00000494383.1 link	c.-10C>T		upstream_gene_variant		2		ENSP00000417517.1		H0Y858

Frequencies

GnomAD3 genomes

AF:

0.0351

AC:

5335

AN:

152090

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00939

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.0460

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.0298

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0307

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0492

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0369

AC:

9271

AN:

251404

AF XY:

0.0373

show subpopulations

Gnomad AFR exome

AF:

0.00818

Gnomad AMR exome

AF:

0.0343

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.0260

Gnomad FIN exome

AF:

0.0331

Gnomad NFE exome

AF:

0.0494

Gnomad OTH exome

AF:

0.0463

GnomAD4 exome

AF:

0.0445

AC:

65035

AN:

1461812

Hom.:

1654

Cov.:

AF XY:

0.0441

AC XY:

32106

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00815

AC:

273

AN:

33480

American (AMR)

AF:

0.0367

AC:

1641

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

699

AN:

26130

East Asian (EAS)

AF:

0.0209

AC:

830

AN:

39700

South Asian (SAS)

AF:

0.0199

AC:

1714

AN:

86258

European-Finnish (FIN)

AF:

0.0339

AC:

1813

AN:

53416

Middle Eastern (MID)

AF:

0.0369

AC:

213

AN:

5766

European-Non Finnish (NFE)

AF:

0.0496

AC:

55147

AN:

1111956

Other (OTH)

AF:

0.0448

AC:

2705

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

3741

7483

11224

14966

18707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2008

4016

6024

8032

10040

<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:

0.0351

AC:

5336

AN:

152208

Hom.:

138

Cov.:

AF XY:

0.0332

AC XY:

2471

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00934

AC:

388

AN:

41532

American (AMR)

AF:

0.0459

AC:

703

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

AN:

3472

East Asian (EAS)

AF:

0.0293

AC:

151

AN:

5160

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4822

European-Finnish (FIN)

AF:

0.0307

AC:

326

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0492

AC:

3345

AN:

67982

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

280

560

840

1120

1400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0452

Hom.:

277

Bravo

AF:

0.0357

Asia WGS

AF:

0.0350

AC:

120

AN:

3478

EpiCase

AF:

0.0496

EpiControl

AF:

0.0539

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.31

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over