Variant 2-238848375-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_001271893.4(TWIST2):c.160G>A(p.Gly54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,534,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

TWIST2
NM_001271893.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.576

Variant links:

Genes affected

TWIST2 (HGNC:20670): (twist family bHLH transcription factor 2) The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found. [provided by RefSeq, Apr 2014]

TWIST2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a chain Twist-related protein 2 (size 159) in uniprot entity TWST2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001271893.4

BP4

Computational evidence support a benign effect (MetaRNN=0.041771114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TWIST2	NM_001271893.4 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	1/2	ENST00000612363.2
TWIST2	NM_057179.3 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	1/2
TWIST2	XR_007069137.1 linkuse as main transcript	n.291G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TWIST2	ENST00000612363.2 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	1/2	1	NM_001271893.4	P1
TWIST2	ENST00000448943.2 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	1/2	1		P1
TWIST2	ENST00000710607.1 linkuse as main transcript	c.160G>A	p.Gly54Ser	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000217

AC:

AN:

138512

Hom.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.000239

GnomAD4 exome

AF:

0.0000297

AC:

AN:

1382674

Hom.:

Cov.:

AF XY:

0.0000367

AC XY:

AN XY:

682094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000371

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.160G>A (p.G54S) alteration is located in exon 1 (coding exon 1) of the TWIST2 gene. This alteration results from a G to A substitution at nucleotide position 160, causing the glycine (G) at amino acid position 54 to be replaced by a serine (S). 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

0.073

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.058

T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.86

.;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.042

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

-2.0

N;N

MutationTaster

Benign

0.51

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.0

N;.

REVEL

Benign

0.28

Sift

Benign

0.96

T;.

Sift4G

Benign

0.90

T;T

Polyphen

0.0

B;B

Vest4

0.10

MutPred

0.22

Gain of phosphorylation at G54 (P = 0.0047);Gain of phosphorylation at G54 (P = 0.0047);

MVP

0.82

MPC

1.6

ClinPred

0.13

GERP RS

4.8

Varity_R

0.079

gMVP

0.30

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over