chr7-115940760-C-G

Position:

• chr7-115940760-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012252.4(TFEC):​c.835G>C​(p.Ala279Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFEC NM_012252.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16016886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFEC	NM_012252.4	c.835G>C	p.Ala279Pro	missense_variant	8/8	ENST00000265440.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFEC	ENST00000265440.12	c.835G>C	p.Ala279Pro	missense_variant	8/8	1	NM_012252.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.835G>C (p.A279P) alteration is located in exon 8 (coding exon 7) of the TFEC gene. This alteration results from a G to C substitution at nucleotide position 835, causing the alanine (A) at amino acid position 279 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	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T;.
Eigen	Benign	0.016
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.92, 0.71	.;P;P
Vest4		0.091
MutPred		0.52		.;Gain of disorder (P = 0.0257);.;
MVP		0.63
MPC		0.27
ClinPred		0.71	D
GERP RS		3.4
Varity_R		0.12
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-115580814;