7-19116526-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
• Publications: 5 publications found

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]

TWIST1 Gene-Disease associations (from GenCC):

• Saethre-Chotzen syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Laboratory for Molecular Medicine
• TWIST1-related craniosynostosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated scaphocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sweeney-Cox syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000474.4. 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
	TWIST1	NM_000474.4	MANE Select	c.*42+145G>T		intron	N/A	NP_000465.1	Q15672
	TWIST1	NR_149001.2		n.966+145G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST1	ENST00000242261.6	TSL:1 MANE Select	c.*42+145G>T		intron	N/A	ENSP00000242261.5	Q15672
	TWIST1	ENST00000354571.5	TSL:2	n.*42+145G>T		intron	N/A	ENSP00000346582.5	H7BY00
	TWIST1	ENST00000443687.5	TSL:4	n.*42+145G>T		intron	N/A	ENSP00000416986.1	H7C4D7

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

African (AFR) AF: 0.0640 AC: 936 AN: 14624

American (AMR) AF: 0.0477 AC: 959 AN: 20088

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 920 AN: 14370

East Asian (EAS) AF: 0.178 AC: 5595 AN: 31382

South Asian (SAS) AF: 0.103 AC: 5085 AN: 49196

European-Finnish (FIN) AF: 0.0294 AC: 862 AN: 29288

Middle Eastern (MID) AF: 0.0762 AC: 167 AN: 2192

European-Non Finnish (NFE) AF: 0.0377 AC: 14021 AN: 371720

Other (OTH) 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

African (AFR) AF: 0.0671 AC: 2785 AN: 41514

American (AMR) AF: 0.0495 AC: 758 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0646 AC: 224 AN: 3470

East Asian (EAS) AF: 0.122 AC: 625 AN: 5122

South Asian (SAS) AF: 0.102 AC: 491 AN: 4828

European-Finnish (FIN) AF: 0.0382 AC: 406 AN: 10616

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2566 AN: 67986

Other (OTH) AF: 0.0442 AC: 93 AN: 2104

Alfa AF: 0.0412 Hom.: 22

Bravo AF: 0.0542

Asia WGS AF: 0.105 AC: 362 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.88
PhyloP100		0.25
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

Other links and lift over

dbSNP: rs4647960; hg19: chr7-19156149;