2-238848438-G-A

Variant names:

• chr2-238848438-G-A
• rs1553565140
• NM_001271893.4:c.223G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 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. 13/22 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:4
• Conservation: PhyloP100: 9.52
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• ablepharon macrostomia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Barber-Say syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• focal facial dermal dysplasia type III

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-238848439-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 208076.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1324 (below the threshold of 3.09). Trascript score misZ: 0.22546 (below the threshold of 3.09). GenCC associations: The gene is linked to ablepharon macrostomia syndrome, focal facial dermal dysplasia type III, Barber-Say syndrome.
• 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 VariationId is 208077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271893.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST2	NM_001271893.4	MANE Select	c.223G>A	p.Glu75Lys	missense	Exon 1 of 2	NP_001258822.1	Q8WVJ9
	TWIST2	NM_057179.3		c.223G>A	p.Glu75Lys	missense	Exon 1 of 2	NP_476527.1	Q8WVJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST2	ENST00000612363.2	TSL:1 MANE Select	c.223G>A	p.Glu75Lys	missense	Exon 1 of 2	ENSP00000482581.1	Q8WVJ9
	TWIST2	ENST00000448943.2	TSL:1	c.223G>A	p.Glu75Lys	missense	Exon 1 of 2	ENSP00000405176.2	Q8WVJ9
	TWIST2	ENST00000710607.1		c.223G>A	p.Glu75Lys	missense	Exon 1 of 2	ENSP00000518373.1	Q8WVJ9

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31744

American (AMR) AF: 0.00 AC: 0 AN: 36218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 36068

South Asian (SAS) AF: 0.00 AC: 0 AN: 79508

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 39940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082610

Other (OTH) AF: 0.00 AC: 0 AN: 58308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Ablepharon macrostomia syndrome (3)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.87		Gain of MoRF binding (P = 0.0234)
MVP		0.95
MPC		3.1
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.085	Neutral
Varity_R		0.84
gMVP		1.0
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

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