rs1275864437

Variant names:

• chr2-238848244-C-A
• rs1275864437
• NM_001271893.4:c.29C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-238848244-C-A
• chr2-238848244-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_001271893.4(TWIST2):​c.29C>A​(p.Ser10Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000447 in 1,343,508 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S10F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: TWIST2 NM_001271893.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.

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.29C>A	p.Ser10Tyr	missense	Exon 1 of 2	NP_001258822.1	Q8WVJ9
	TWIST2	NM_057179.3		c.29C>A	p.Ser10Tyr	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.29C>A	p.Ser10Tyr	missense	Exon 1 of 2	ENSP00000482581.1	Q8WVJ9
	TWIST2	ENST00000448943.2	TSL:1	c.29C>A	p.Ser10Tyr	missense	Exon 1 of 2	ENSP00000405176.2	Q8WVJ9
	TWIST2	ENST00000710607.1		c.29C>A	p.Ser10Tyr	missense	Exon 1 of 2	ENSP00000518373.1	Q8WVJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 112826 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000447 AC: 6 AN: 1343508 Hom.: 0 Cov.: 31 AF XY: 0.00000609 AC XY: 4 AN XY: 657066

African (AFR) AF: 0.00 AC: 0 AN: 29674

American (AMR) AF: 0.00 AC: 0 AN: 33722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24018

East Asian (EAS) AF: 0.00 AC: 0 AN: 33554

South Asian (SAS) AF: 0.00 AC: 0 AN: 75560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4808

European-Non Finnish (NFE) AF: 0.00000380 AC: 4 AN: 1053360

Other (OTH) AF: 0.0000358 AC: 2 AN: 55942

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.24		Loss of phosphorylation at S10 (P = 0.043)
MVP		0.99
MPC		3.0
ClinPred		0.96	D
GERP RS		4.7
PromoterAI		-0.073	Neutral
Varity_R		0.30
gMVP		0.78
Mutation Taster		=63/37	polymorphism

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: rs1275864437; hg19: chr2-239756885;