chr8-66961536-G-A

Variant names:

• chr8-66961536-G-A
• rs1814254049
• NM_001193502.2:c.230C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001193502.2(TCF24):​c.230C>T​(p.Pro77Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P77R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF24 NM_001193502.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09
• Publications: 0 publications found

Genes affected

TCF24 (HGNC:32275): (transcription factor 24) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in developmental process and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193502.2. 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
	TCF24	NM_001193502.2	MANE Select	c.230C>T	p.Pro77Leu	missense	Exon 3 of 4	NP_001180431.1	Q7RTU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF24	ENST00000563496.2	TSL:5 MANE Select	c.230C>T	p.Pro77Leu	missense	Exon 3 of 4	ENSP00000455444.1	Q7RTU0
	TCF24	ENST00000929798.1		c.230C>T	p.Pro77Leu	missense	Exon 2 of 3	ENSP00000599857.1
	TCF24	ENST00000929799.1		c.230C>T	p.Pro77Leu	missense	Exon 2 of 3	ENSP00000599858.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1358046 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 669984

African (AFR) AF: 0.00 AC: 0 AN: 27974

American (AMR) AF: 0.00 AC: 0 AN: 33264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24262

East Asian (EAS) AF: 0.00 AC: 0 AN: 31848

South Asian (SAS) AF: 0.00 AC: 0 AN: 76508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5384

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068586

Other (OTH) AF: 0.00 AC: 0 AN: 56838

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-10	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.68
MVP		0.88
GERP RS		4.3
Varity_R		0.78
gMVP		0.83
Mutation Taster		=15/85	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

dbSNP: rs1814254049; hg19: chr8-67873771;