chr20-609775-C-A

Variant names:

• chr20-609775-C-A
• rs1354210845
• NM_004609.4:c.463G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004609.4(TCF15):​c.463G>T​(p.Ala155Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000794 in 1,259,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A155P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TCF15 NM_004609.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047696203).

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.463G>T	p.Ala155Ser	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.463G>T	p.Ala155Ser	missense	Exon 1 of 2	ENSP00000246080.3	Q12870

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.94e-7 AC: 1 AN: 1259962 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 618822

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24976

American (AMR) AF: 0.00 AC: 0 AN: 13656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19126

East Asian (EAS) AF: 0.00 AC: 0 AN: 28018

South Asian (SAS) AF: 0.0000169 AC: 1 AN: 59148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3950

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1028260

Other (OTH) AF: 0.00 AC: 0 AN: 51970

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.2
DANN	Benign	0.94
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.22
Sift	Benign	0.86	T
Sift4G	Benign	0.73	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.28		Loss of relative solvent accessibility (P = 0.0404)
MVP		0.16
MPC		1.1
ClinPred		0.19	T
GERP RS		-1.2
Varity_R		0.048
gMVP		0.24
Mutation Taster		=94/6	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: rs1354210845; hg19: chr20-590419;