20-609753-C-T

Variant names:

• chr20-609753-C-T
• NM_004609.4:c.485G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004609.4(TCF15):​c.485G>A​(p.Arg162His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF15 NM_004609.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

Genes affected

TCF15 (HGNC:11627): (transcription factor 15) The protein encoded by this gene is found in the nucleus and may be involved in the early transcriptional regulation of patterning of the mesoderm. The encoded basic helix-loop-helix protein requires dimerization with another basic helix-loop-helix protein for efficient DNA binding. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004609.4. 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
	TCF15	NM_004609.4	MANE Select	c.485G>A	p.Arg162His	missense	Exon 1 of 2	NP_004600.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF15	ENST00000246080.4	TSL:1 MANE Select	c.485G>A	p.Arg162His	missense	Exon 1 of 2	ENSP00000246080.3	Q12870

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1254002 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 615464

African (AFR) AF: 0.00 AC: 0 AN: 24490

American (AMR) AF: 0.00 AC: 0 AN: 13102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18986

East Asian (EAS) AF: 0.00 AC: 0 AN: 27700

South Asian (SAS) AF: 0.00 AC: 0 AN: 58624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4448

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1024450

Other (OTH) AF: 0.00 AC: 0 AN: 51724

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.42		Loss of helix (P = 0.0068)
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.44
gMVP		0.40
Mutation Taster		=26/74	disease causing

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

hg19: chr20-590397;