6-31161488-C-A

Variant names:

• chr6-31161488-C-A
• rs201756282
• NM_007109.3:c.280C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_007109.3(TCF19):​c.280C>A​(p.Leu94Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000755 in 1,483,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: TCF19 NM_007109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.745
• Publications: 0 publications found

Genes affected

TCF19 (HGNC:11629): (transcription factor 19) This gene encodes a protein that contains a PHD-type zinc finger domain and likely functions as a transcription factor. The encoded protein plays a role proliferation and apoptosis of pancreatic beta cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04293096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF19	NM_007109.3	c.280C>A	p.Leu94Met	missense_variant	Exon 3 of 4	ENST00000376257.8	NP_009040.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF19	ENST00000376257.8	c.280C>A	p.Leu94Met	missense_variant	Exon 3 of 4	1	NM_007109.3	ENSP00000365433.3

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000104 AC: 16 AN: 154204 AF XY: 0.0000718

Gnomad AFR exome AF: 0.000958

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000812

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.000307

GnomAD4 exome AF: 0.0000586 AC: 78 AN: 1330834 Hom.: 0 Cov.: 29 AF XY: 0.0000506 AC XY: 33 AN XY: 651662

African (AFR) AF: 0.00200 AC: 57 AN: 28554

American (AMR) AF: 0.0000397 AC: 1 AN: 25188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19260

East Asian (EAS) AF: 0.00 AC: 0 AN: 35790

South Asian (SAS) AF: 0.0000462 AC: 3 AN: 64872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48620

Middle Eastern (MID) AF: 0.000384 AC: 2 AN: 5214

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1048908

Other (OTH) AF: 0.000239 AC: 13 AN: 54428

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74370

African (AFR) AF: 0.000748 AC: 31 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

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

Alfa AF: 0.000234 Hom.: 1

Bravo AF: 0.000230

ESP6500AA AF: 0.000844 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000121 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280C>A (p.L94M) alteration is located in exon 3 (coding exon 2) of the TCF19 gene. This alteration results from a C to A substitution at nucleotide position 280, causing the leucine (L) at amino acid position 94 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.64	.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.69	N;N;.
PhyloP100		0.74
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.11	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.88	P;P;.
Vest4		0.28
MVP		0.66
MPC		1.4
ClinPred		0.076	T
GERP RS		3.8
PromoterAI		0.013	Neutral
Varity_R		0.16
gMVP		0.23
Mutation Taster		=95/5	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: rs201756282; hg19: chr6-31129265;