6-31161486-G-A

Variant names:

• chr6-31161486-G-A
• rs144374591
• NM_007109.3:c.278G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007109.3(TCF19):​c.278G>A​(p.Arg93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,481,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TCF19 NM_007109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.118673235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF19	NM_007109.3	c.278G>A	p.Arg93Lys	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.278G>A	p.Arg93Lys	missense_variant	Exon 3 of 4	1	NM_007109.3	ENSP00000365433.3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000391 AC: 6 AN: 153580 AF XY: 0.0000361

Gnomad AFR exome AF: 0.000523

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 22 AN: 1329404 Hom.: 0 Cov.: 29 AF XY: 0.0000154 AC XY: 10 AN XY: 650856

African (AFR) AF: 0.000701 AC: 20 AN: 28512

American (AMR) AF: 0.00 AC: 0 AN: 25072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19230

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.00 AC: 0 AN: 64610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5204

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1048158

Other (OTH) AF: 0.0000184 AC: 1 AN: 54344

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74504

African (AFR) AF: 0.000409 AC: 17 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000421 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000259 AC: 3

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

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.278G>A (p.R93K) alteration is located in exon 3 (coding exon 2) of the TCF19 gene. This alteration results from a G to A substitution at nucleotide position 278, causing the arginine (R) at amino acid position 93 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.098	T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		2.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.89	P;P;.
Vest4		0.13
MVP		0.82
MPC		1.1
ClinPred		0.12	T
GERP RS		4.7
PromoterAI		0.010	Neutral
Varity_R		0.26
gMVP		0.36
Mutation Taster		=89/11	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: rs144374591; hg19: chr6-31129263;