rs387906974

Variant names:

• chr2-238848408-C-T
• rs387906974
• NM_001271893.4:c.193C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001271893.4(TWIST2):​c.193C>T​(p.Gln65*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TWIST2 NM_001271893.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.54
• Publications: 4 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Barber-Say syndrome

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

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-238848408-C-T is Pathogenic according to our data. Variant chr2-238848408-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30679.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST2	NM_001271893.4	c.193C>T	p.Gln65*	stop_gained	Exon 1 of 2	ENST00000612363.2	NP_001258822.1
TWIST2	NM_057179.3	c.193C>T	p.Gln65*	stop_gained	Exon 1 of 2		NP_476527.1
TWIST2	XR_007069137.1	n.324C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWIST2	ENST00000612363.2	c.193C>T	p.Gln65*	stop_gained	Exon 1 of 2	1	NM_001271893.4	ENSP00000482581.1
TWIST2	ENST00000448943.2	c.193C>T	p.Gln65*	stop_gained	Exon 1 of 2	1		ENSP00000405176.2
TWIST2	ENST00000710607.1	c.193C>T	p.Gln65*	stop_gained	Exon 1 of 2			ENSP00000518373.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1385516 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683690

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078954

Other (OTH) AF: 0.00 AC: 0 AN: 57956

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Focal facial dermal dysplasia type III Pathogenic:1

Aug 13, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		7.5
Vest4		0.81
GERP RS		4.8
PromoterAI		-0.054	Neutral
Mutation Taster		=12/188	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: rs387906974; hg19: chr2-239757049;