chr6-31161765-G-A

Variant names:

• chr6-31161765-G-A
• rs188298136
• NM_007109.3:c.557G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007109.3(TCF19):​c.557G>A​(p.Arg186Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,600,312 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (7 hom.)
• Consequence: TCF19 NM_007109.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.773
• Publications: 4 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014848709).
• BP6: Variant 6-31161765-G-A is Benign according to our data. Variant chr6-31161765-G-A is described in ClinVar as [Benign]. Clinvar id is 714312.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (898/152312) while in subpopulation AFR AF = 0.0191 (792/41556). AF 95% confidence interval is 0.018. There are 12 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF19	NM_007109.3	c.557G>A	p.Arg186Gln	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.557G>A	p.Arg186Gln	missense_variant	Exon 3 of 4	1	NM_007109.3	ENSP00000365433.3

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152194 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00152 AC: 356 AN: 234754 AF XY: 0.00120

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000791 AC: 1146 AN: 1448000 Hom.: 7 Cov.: 31 AF XY: 0.000758 AC XY: 545 AN XY: 719060

African (AFR) AF: 0.0182 AC: 603 AN: 33204

American (AMR) AF: 0.00185 AC: 81 AN: 43668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.000154 AC: 13 AN: 84176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51836

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5692

European-Non Finnish (NFE) AF: 0.000321 AC: 355 AN: 1105098

Other (OTH) AF: 0.00147 AC: 88 AN: 59828

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152312 Hom.: 12 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74480

African (AFR) AF: 0.0191 AC: 792 AN: 41556

American (AMR) AF: 0.00497 AC: 76 AN: 15304

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00223 Hom.: 8

Bravo AF: 0.00705

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0174 AC: 44

ESP6500EA AF: 0.000394 AC: 2

ExAC AF: 0.00167 AC: 195

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.7
DANN	Benign	0.81
DEOGEN2	Benign	0.00045	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.61	.;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.23	N;N;.
PhyloP100		-0.77
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.14	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.67	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.030
MVP		0.076
MPC		0.58
ClinPred		0.0013	T
GERP RS		-7.2
PromoterAI		0.0076	Neutral
Varity_R		0.026
gMVP		0.089
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs188298136; hg19: chr6-31129542;