chr3-52229976-C-T

Variant names:

• chr3-52229976-C-T
• rs1360202184
• NM_007284.4:c.704G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007284.4(TWF2):​c.704G>A​(p.Arg235His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TWF2 NM_007284.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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]

ENSG00000173366 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWF2	NM_007284.4	c.704G>A	p.Arg235His	missense_variant	Exon 7 of 9	ENST00000305533.10	NP_009215.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWF2	ENST00000305533.10	c.704G>A	p.Arg235His	missense_variant	Exon 7 of 9	1	NM_007284.4	ENSP00000303908.4
ENSG00000173366	ENST00000494383.1	c.284G>A	p.Arg95His	missense_variant	Exon 3 of 5	2		ENSP00000417517.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.704G>A (p.R235H) alteration is located in exon 7 (coding exon 7) of the TWF2 gene. This alteration results from a G to A substitution at nucleotide position 704, causing the arginine (R) at amino acid position 235 to be replaced by a histidine (H). 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	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.041	D;T
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.83		Loss of catalytic residue at R235 (P = 0.0231);Loss of catalytic residue at R235 (P = 0.0231);
MVP		0.55
MPC		1.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.72
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs1360202184; hg19: chr3-52263992;