rs1554442016

Positions:

• chr7-19116972-T-A
• chr7-19116972-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000242261.6(TWIST1):​c.350A>T​(p.Glu117Val) variant causes a missense change. 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 no classifications from unflagged records (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TWIST1 ENST00000242261.6 missense
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 6.03

Genes affected

TWIST1 (HGNC:12428): (twist family bHLH transcription factor 1) This gene encodes a basic helix-loop-helix (bHLH) transcription factor that plays an important role in embryonic development. The encoded protein forms both homodimers and heterodimers that bind to DNA E box sequences and regulate the transcription of genes involved in cranial suture closure during skull development. This protein may also regulate neural tube closure, limb development and brown fat metabolism. This gene is hypermethylated and overexpressed in multiple human cancers, and the encoded protein promotes tumor cell invasion and metastasis, as well as metastatic recurrence. Mutations in this gene cause Saethre-Chotzen syndrome in human patients, which is characterized by craniosynostosis, ptosis and hypertelorism. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000242261.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-19116971-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2572412.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-19116972-T-A is Pathogenic according to our data. Variant chr7-19116972-T-A is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 444875.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.350A>T	p.Glu117Val	missense_variant	1/2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.665A>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.350A>T	p.Glu117Val	missense_variant	1/2	1	NM_000474.4	ENSP00000242261	P1
TWIST1	ENST00000354571.5	c.149A>T	p.Glu50Val	missense_variant, NMD_transcript_variant	1/3	2		ENSP00000346582
TWIST1	ENST00000443687.5			upstream_gene_variant		4		ENSP00000416986

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

Submissions by phenotype

Sweeney-Cox syndrome Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Oct 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.90		Loss of disorder (P = 0.0658);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554442016; hg19: chr7-19156595;