chr7-19116526-C-A

Variant names:

• chr7-19116526-C-A
• rs4647960
• NM_000474.4:c.*42+145G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000474.4(TWIST1):​c.*42+145G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 714,670 control chromosomes in the GnomAD database, including 1,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (283 hom., cov: 32)
  • Exomes 𝑓: 0.053 (1287 hom.)
• Consequence: TWIST1 NM_000474.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.251

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-19116526-C-A is Benign according to our data. Variant chr7-19116526-C-A is described in ClinVar as [Benign]. Clinvar id is 1272414.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWIST1	NM_000474.4	c.*42+145G>T		intron_variant	Intron 1 of 1	ENST00000242261.6	NP_000465.1
TWIST1	NR_149001.2	n.966+145G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWIST1	ENST00000242261.6	c.*42+145G>T		intron_variant	Intron 1 of 1	1	NM_000474.4	ENSP00000242261.5
TWIST1	ENST00000354571.5	n.*42+145G>T		intron_variant	Intron 1 of 2	2		ENSP00000346582.5
TWIST1	ENST00000443687.5	n.*42+145G>T		intron_variant	Intron 1 of 3	4		ENSP00000416986.1

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8064 AN: 152028 Hom.: 282 Cov.: 32

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0447

GnomAD4 exome AF: 0.0534 AC: 30052 AN: 562524 Hom.: 1287 AF XY: 0.0558 AC XY: 16270 AN XY: 291458

Gnomad4 AFR exome AF: 0.0640 AC: 936 AN: 14624

Gnomad4 AMR exome AF: 0.0477 AC: 959 AN: 20088

Gnomad4 ASJ exome AF: 0.0640 AC: 920 AN: 14370

Gnomad4 EAS exome AF: 0.178 AC: 5595 AN: 31382

Gnomad4 SAS exome AF: 0.103 AC: 5085 AN: 49196

Gnomad4 FIN exome AF: 0.0294 AC: 862 AN: 29288

Gnomad4 NFE exome AF: 0.0377 AC: 14021 AN: 371720

Gnomad4 Remaining exome AF: 0.0508 AC: 1507 AN: 29664

GnomAD4 genome AF: 0.0531 AC: 8072 AN: 152146 Hom.: 283 Cov.: 32 AF XY: 0.0542 AC XY: 4034 AN XY: 74400

Gnomad4 AFR AF: 0.0671 AC: 0.0670858 AN: 0.0670858

Gnomad4 AMR AF: 0.0495 AC: 0.0495425 AN: 0.0495425

Gnomad4 ASJ AF: 0.0646 AC: 0.0645533 AN: 0.0645533

Gnomad4 EAS AF: 0.122 AC: 0.122023 AN: 0.122023

Gnomad4 SAS AF: 0.102 AC: 0.101698 AN: 0.101698

Gnomad4 FIN AF: 0.0382 AC: 0.0382442 AN: 0.0382442

Gnomad4 NFE AF: 0.0377 AC: 0.0377431 AN: 0.0377431

Gnomad4 OTH AF: 0.0442 AC: 0.0442015 AN: 0.0442015

Alfa AF: 0.0412 Hom.: 22

Bravo AF: 0.0542

Asia WGS AF: 0.105 AC: 362 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs4647960; hg19: chr7-19156149;