7-19117228-C-T

Variant names:

• chr7-19117228-C-T
• rs878852992
• NM_000474.4:c.94G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BP6 BS2

The NM_000474.4(TWIST1):​c.94G>A​(p.Gly32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,413,900 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G32R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: TWIST1 NM_000474.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 0.109
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a chain Twist-related protein 1 (size 201) in uniprot entity TWST1_HUMAN there are 40 pathogenic changes around while only 6 benign (87%) in NM_000474.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.057 (below the threshold of 3.09). Trascript score misZ: -0.22696 (below the threshold of 3.09). GenCC associations: The gene is linked to Saethre-Chotzen syndrome, isolated brachycephaly, TWIST1-related craniosynostosis, Sweeney-Cox syndrome, isolated plagiocephaly, isolated scaphocephaly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40579277).
• BP6: Variant 7-19117228-C-T is Benign according to our data. Variant chr7-19117228-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235255.
• BS2: High AC in GnomAd4 at 163 AD gene.

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.94G>A	p.Gly32Ser	missense	Exon 1 of 2	NP_000465.1	Q15672
	TWIST1	NR_149001.2		n.409G>A		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWIST1	ENST00000242261.6	TSL:1 MANE Select	c.94G>A	p.Gly32Ser	missense	Exon 1 of 2	ENSP00000242261.5	Q15672
	TWIST1	ENST00000354571.5	TSL:2	n.-111G>A		upstream_gene	N/A	ENSP00000346582.5	H7BY00

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 163 AN: 151162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.00120 AC: 93 AN: 77226 AF XY: 0.00120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000419

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.00249 AC: 3150 AN: 1262738 Hom.: 7 Cov.: 31 AF XY: 0.00241 AC XY: 1500 AN XY: 622590

African (AFR) AF: 0.000350 AC: 9 AN: 25716

American (AMR) AF: 0.000398 AC: 10 AN: 25156

Ashkenazi Jewish (ASJ) AF: 0.000515 AC: 11 AN: 21362

East Asian (EAS) AF: 0.00 AC: 0 AN: 25986

South Asian (SAS) AF: 0.0000444 AC: 3 AN: 67572

European-Finnish (FIN) AF: 0.000337 AC: 10 AN: 29668

Middle Eastern (MID) AF: 0.000554 AC: 2 AN: 3610

European-Non Finnish (NFE) AF: 0.00294 AC: 2973 AN: 1012896

Other (OTH) AF: 0.00260 AC: 132 AN: 50772

GnomAD4 genome AF: 0.00108 AC: 163 AN: 151162 Hom.: 0 Cov.: 32 AF XY: 0.00100 AC XY: 74 AN XY: 73786

African (AFR) AF: 0.000508 AC: 21 AN: 41348

American (AMR) AF: 0.000132 AC: 2 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00205 AC: 139 AN: 67720

Other (OTH) AF: 0.000483 AC: 1 AN: 2070

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.00117

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	1	not specified (2)
-	1	-	Saethre-Chotzen syndrome;C1867146:Robinow-Sorauf syndrome;C4540299:Sweeney-Cox syndrome;C4551902:TWIST1-related craniosynostosis (1)
-	-	1	Saethre-Chotzen syndrome;C4551902:TWIST1-related craniosynostosis (1)
-	-	1	TWIST1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.11
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.53
Sift	Benign	0.89	T
Sift4G	Benign	0.70	T
Polyphen		0.012	B
Vest4		0.69
MVP		0.99
MPC		1.4
ClinPred		0.031	T
GERP RS		3.7
PromoterAI		-0.017	Neutral
Varity_R		0.084
gMVP		0.25
Mutation Taster		=74/26	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: rs878852992; hg19: chr7-19156851;