6-31161605-G-C

Variant names:

• chr6-31161605-G-C
• NM_007109.3:c.397G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007109.3(TCF19):​c.397G>C​(p.Ala133Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCF19 NM_007109.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF19	NM_007109.3	c.397G>C	p.Ala133Pro	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.397G>C	p.Ala133Pro	missense_variant	Exon 3 of 4	1	NM_007109.3	ENSP00000365433.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.397G>C (p.A133P) alteration is located in exon 3 (coding exon 2) of the TCF19 gene. This alteration results from a G to C substitution at nucleotide position 397, causing the alanine (A) at amino acid position 133 to be replaced by a proline (P). 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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	M;M;.
PhyloP100		5.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N;N;D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.67
MutPred		0.37		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;
MVP		0.72
MPC		1.6
ClinPred		0.98	D
GERP RS		5.7
PromoterAI		-0.035	Neutral
Varity_R		0.56
gMVP		0.78
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

hg19: chr6-31129382;