18-55461060-T-C

Position:

• chr18-55461060-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_001083962.2(TCF4):​c.263A>G​(p.His88Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.13

Genes affected

TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

TCF4-AS1 (HGNC:51642): (TCF4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TCF4. . Gene score misZ 4.1035 (greater than the threshold 3.09). Trascript score misZ 4.5676 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, corneal dystrophy, Fuchs endothelial, 3, autosomal dominant non-syndromic intellectual disability, autism spectrum disorder, Fuchs' endothelial dystrophy, Pitt-Hopkins syndrome.
• BP6: Variant 18-55461060-T-C is Benign according to our data. Variant chr18-55461060-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2996306.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2	c.263A>G	p.His88Arg	missense_variant	5/20	ENST00000354452.8	NP_001077431.1
TCF4-AS1	NR_132985.1	n.178+8350T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8	c.263A>G	p.His88Arg	missense_variant	5/20	5	NM_001083962.2	ENSP00000346440	P3
TCF4-AS1	ENST00000587660.1	n.178+8350T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pitt-Hopkins syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D;.;T;.;D;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;.;.;D;D;D;.;D;.;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.0	.;M;.;.;.;M;M;M;.;.;.;.;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.95	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;D;D;.;D;D;D;D;D;D;.;D;N;D;D;.;D;.;.;.;.;D;.;D;D;.;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	.;D;.;.;.;D;D;.;D;D;D;D;D;D;.;D;T;D;D;.;D;.;.;.;.;D;.;D;D;.;D;D
Sift4G	Benign	0.16	T;T;.;.;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;D;D;D;.;.;D;D;D;.;.
Polyphen		0.88, 0.94	.;P;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.66
MutPred		0.18		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at S189 (P = 0.0962);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.90
MPC		0.72
ClinPred		0.93	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs1327666670; hg19: chr18-53128291;