7-115956763-C-T

Position:

• chr7-115956763-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012252.4(TFEC):​c.298G>A​(p.Gly100Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,596,094 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (44 hom.)
• Consequence: TFEC NM_012252.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.86

Genes affected

TFEC (HGNC:11754): (transcription factor EC) This gene encodes a member of the micropthalmia (MiT) family of basic helix-loop-helix leucine zipper transcription factors. MiT transcription factors regulate the expression of target genes by binding to E-box recognition sequences as homo- or heterodimers, and play roles in multiple cellular processes including survival, growth and differentiation. The encoded protein is a transcriptional activator of the nonmuscle myosin II heavy chain-A gene, and may also co-regulate target genes in osteoclasts as a heterodimer with micropthalmia-associated transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

TFEC (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019370317).
• BP6: Variant 7-115956763-C-T is Benign according to our data. Variant chr7-115956763-C-T is described in ClinVar as [Benign]. Clinvar id is 768196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFEC	NM_012252.4	c.298G>A	p.Gly100Ser	missense_variant	4/8	ENST00000265440.12	NP_036384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFEC	ENST00000265440.12	c.298G>A	p.Gly100Ser	missense_variant	4/8	1	NM_012252.4	ENSP00000265440.7

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2314 AN: 151780 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00697

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00817

GnomAD3 exomes AF: 0.00396 AC: 969 AN: 244600 Hom.: 21 AF XY: 0.00280 AC XY: 371 AN XY: 132286

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00186

GnomAD4 exome AF: 0.00157 AC: 2269 AN: 1444196 Hom.: 44 Cov.: 30 AF XY: 0.00134 AC XY: 960 AN XY: 718216

Gnomad4 AFR exome AF: 0.0539

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.000469

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000726

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.0152 AC: 2314 AN: 151898 Hom.: 56 Cov.: 32 AF XY: 0.0147 AC XY: 1093 AN XY: 74238

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.00697

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00809

Alfa AF: 0.00212 Hom.: 10

Bravo AF: 0.0171

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00447 AC: 542

Asia WGS AF: 0.00116 AC: 4 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.18	.;T;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.83	T;T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T
Polyphen		0.10, 0.20, 0.44, 0.76	.;B;B;B;P
Vest4		0.16
MVP		0.22
MPC		0.043
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.035
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs35170691; hg19: chr7-115596817;