chr7-19116723-G-T

Variant names:

• chr7-19116723-G-T
• NM_000474.4:c.599C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000474.4(TWIST1):​c.599C>A​(p.Ala200Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TWIST1 NM_000474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.66

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 17 pathogenic changes around while only 3 benign (85%) in NM_000474.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.599C>A	p.Ala200Glu	missense_variant	Exon 1 of 2	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.914C>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.599C>A	p.Ala200Glu	missense_variant	Exon 1 of 2	1	NM_000474.4	ENSP00000242261.5
TWIST1	ENST00000354571.5	n.395C>A		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000346582.5
TWIST1	ENST00000443687.5	n.200C>A		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000416986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723688

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: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.11	T
Polyphen		0.89	P
Vest4		0.48
MutPred		0.25		Loss of MoRF binding (P = 0.0067);
MVP		1.0
MPC		2.1
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.54
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-19156346;