2-238848438-G-A

Position:

• chr2-238848438-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001271893.4(TWIST2):​c.223G>A​(p.Glu75Lys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E75A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TWIST2 NM_001271893.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain bHLH (size 51) in uniprot entity TWST2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001271893.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-238848438-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 208078.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-238848438-G-A is Pathogenic according to our data. Variant chr2-238848438-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWIST2	NM_001271893.4	c.223G>A	p.Glu75Lys	missense_variant	1/2	ENST00000612363.2
TWIST2	NM_057179.3	c.223G>A	p.Glu75Lys	missense_variant	1/2
TWIST2	XR_007069137.1	n.354G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWIST2	ENST00000612363.2	c.223G>A	p.Glu75Lys	missense_variant	1/2	1	NM_001271893.4	P1
TWIST2	ENST00000448943.2	c.223G>A	p.Glu75Lys	missense_variant	1/2	1		P1
TWIST2	ENST00000710607.1	c.223G>A	p.Glu75Lys	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.17e-7 AC: 1 AN: 1395318 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689052

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: 0.0000250

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ablepharon macrostomia syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pediatrics, Prince of Songkla University	Jun 07, 2020	A heterozygous missense p.Glu75Lys was reported to be associated with Ablepharon macrostomia syndrome in 7 families (Marchegiani et al. 2015). This variant was not found in ExAC database and our in-house Thai exome database (consisted of 1084 Thai exome controls). We classified this as pathogenic variant by ACMG Guidelines, 2015 based on >/=2 strong criteria [PS1, PS2, and PS3 (Functional study by Marchegiani et al. 2015)]. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.87		Gain of MoRF binding (P = 0.0234);Gain of MoRF binding (P = 0.0234);
MVP		0.95
MPC		3.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.84
gMVP		1.0

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

Other links and lift over

dbSNP: rs1553565140; hg19: chr2-239757079; COSMIC: COSV71820612;