Genetic Variant TWIST2:p.Arg28His (chr2-238848298-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001271893.4(TWIST2):c.83G>A(p.Arg28His) variant causes a missense change. The variant allele was found at a frequency of 0.00000362 in 1,380,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

TWIST2
NM_001271893.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.37

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:

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ACMG classification

Classification made for transcript

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=0.23239774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST2	NM_001271893.4 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2	ENST00000612363.2	NP_001258822.1	Q8WVJ9A1MB48
TWIST2	NM_057179.3 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2		NP_476527.1	Q8WVJ9A1MB48
TWIST2	XR_007069137.1 link	n.214G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TWIST2	ENST00000612363.2 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1	Q8WVJ9
TWIST2	ENST00000448943.2 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2	1		ENSP00000405176.2	Q8WVJ9
TWIST2	ENST00000710607.1 link	c.83G>A	p.Arg28His	missense_variant	Exon 1 of 2			ENSP00000518373.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000362

AC:

AN:

1380922

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

680950

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000464

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TWIST2 p.Arg28His variant was not identified in the literature nor was it identified in dbSNP, ClinVar, Cosmic or LOVD 3.0. The variant was also not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg28 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.6

L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.43

Sift

Benign

0.035

D;.

Sift4G

Benign

0.073

T;T

Polyphen

0.0090

B;B

Vest4

0.091

MutPred

0.32

Loss of MoRF binding (P = 0.0519);Loss of MoRF binding (P = 0.0519);

MVP

1.0

MPC

1.9

ClinPred

0.91

GERP RS

4.9

Varity_R

0.19

gMVP

0.73

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over