rs766179873

Variant names:

• chr16-89884655-C-T
• rs766179873
• NM_014972.3:c.428C>T

Variant summary

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

The NM_014972.3(TCF25):​c.428C>T​(p.Ser143Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S143P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TCF25 NM_014972.3 missense, splice_region
• Scores: Splicing: ADA: 0.001278
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32
• Publications: 1 publications found

Genes affected

TCF25 (HGNC:29181): (transcription factor 25) TCF25 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that are important in embryonic development (Steen and Lindholm, 2008 [PubMed 18068114]).[supplied by OMIM, Sep 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=0.06277603).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014972.3. 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
	TCF25	NM_014972.3	MANE Select	c.428C>T	p.Ser143Leu	missense splice_region	Exon 3 of 18	NP_055787.1	Q9BQ70

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF25	ENST00000263346.13	TSL:1 MANE Select	c.428C>T	p.Ser143Leu	missense splice_region	Exon 3 of 18	ENSP00000263346.8	Q9BQ70
	TCF25	ENST00000562256.5	TSL:1	c.11C>T	p.Ser4Leu	missense splice_region	Exon 1 of 17	ENSP00000455611.1	H3BQ53
	TCF25	ENST00000263347.11	TSL:5	c.-278C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 19	ENSP00000263347.7	Q9H384

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246686 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459366 Hom.: 0 Cov.: 32 AF XY: 0.00000827 AC XY: 6 AN XY: 725832

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.0000450 AC: 2 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110600

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

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

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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	Benign	0.065
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.085
Sift	Benign	0.30	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.23		Loss of phosphorylation at S143 (P = 0.0132)
MVP		0.19
MPC		0.13
ClinPred		0.022	T
GERP RS		-3.2
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.073
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.040		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: rs766179873; hg19: chr16-89951063; COSMIC: COSV54526302; COSMIC: COSV54526302;