12-43797409-G-T

Position:

• chr12-43797409-G-T

Variant summary

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

The NM_002822.5(TWF1):​c.653C>A​(p.Thr218Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWF1 NM_002822.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

Genes affected

TWF1 (HGNC:9620): (twinfilin actin binding protein 1) This gene encodes twinfilin, an actin monomer-binding protein conserved from yeast to mammals. Studies of the mouse counterpart suggest that this protein may be an actin monomer-binding protein, and its localization to cortical G-actin-rich structures may be regulated by the small GTPase RAC1. [provided by RefSeq, Jul 2008]

TMEM117 (HGNC:25308): (transmembrane protein 117) Involved in intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress. Located in endoplasmic reticulum and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TWF1 (HGNC:):

IRAK4 (HGNC:17967): (interleukin 1 receptor associated kinase 4) This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

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=0.08166787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWF1	NM_002822.5	c.653C>A	p.Thr218Lys	missense_variant	7/9	ENST00000395510.7	NP_002813.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWF1	ENST00000395510.7	c.653C>A	p.Thr218Lys	missense_variant	7/9	1	NM_002822.5	ENSP00000378886.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2022

The c.674C>A (p.T225K) alteration is located in exon 8 (coding exon 8) of the TWF1 gene. This alteration results from a C to A substitution at nucleotide position 674, causing the threonine (T) at amino acid position 225 to be replaced by a lysine (K). 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	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.70
DEOGEN2	Benign	0.042	.;T;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.38	.;N;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.32	N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.84	T;T;T;T
Sift4G	Benign	0.89	T;T;T;.
Polyphen		0.0010, 0.0	.;B;B;.
Vest4		0.14
MutPred		0.45		.;Gain of solvent accessibility (P = 0.007);.;.;
MVP		0.37
MPC		0.45
ClinPred		0.038	T
GERP RS		2.5
Varity_R		0.023
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-44191212;