6-31162497-G-T

Variant names:

• chr6-31162497-G-T
• rs371901587
• NM_007109.3:c.818G>T

Variant summary

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

The NM_007109.3(TCF19):​c.818G>T​(p.Arg273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,012 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. 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. R273Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF19 NM_007109.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.371
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053862095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007109.3. 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
	TCF19	NM_007109.3	MANE Select	c.818G>T	p.Arg273Leu	missense	Exon 4 of 4	NP_009040.2	A0A1U9X8M7
	TCF19	NM_001077511.2		c.818G>T	p.Arg273Leu	missense	Exon 4 of 4	NP_001070979.1	A0A1U9X8M7
	TCF19	NM_001318908.2		c.818G>T	p.Arg273Leu	missense	Exon 5 of 5	NP_001305837.1	Q9Y242

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF19	ENST00000376257.8	TSL:1 MANE Select	c.818G>T	p.Arg273Leu	missense	Exon 4 of 4	ENSP00000365433.3	Q9Y242
	TCF19	ENST00000376255.4	TSL:1	c.818G>T	p.Arg273Leu	missense	Exon 4 of 4	ENSP00000365431.4	Q9Y242
	TCF19	ENST00000706778.1		c.818G>T	p.Arg273Leu	missense	Exon 5 of 5	ENSP00000516543.1	Q9Y242

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.00000414 AC: 1 AN: 241370 AF XY: 0.00

Gnomad AFR exome AF: 0.0000699

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458938 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725700

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110984

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74244

African (AFR) AF: 0.0000725 AC: 3 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000856 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.37
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.048
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.016	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.26		Loss of methylation at R273 (P = 0.0132)
MVP		0.17
MPC		1.3
ClinPred		0.96	D
GERP RS		0.43
Varity_R		0.25
gMVP		0.71
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs371901587; hg19: chr6-31130274;