NM_012252.4:c.763G>A

Variant names:

• chr7-115940832-C-T
• rs1236936299
• NM_012252.4:c.763G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012252.4(TFEC):​c.763G>A​(p.Glu255Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 5.58
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31659907).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012252.4. 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
	TFEC	NM_012252.4	MANE Select	c.763G>A	p.Glu255Lys	missense	Exon 8 of 8	NP_036384.1	O14948-1
	TFEC	NM_001018058.3		c.676G>A	p.Glu226Lys	missense	Exon 7 of 7	NP_001018068.1	O14948-2
	TFEC	NM_001244583.2		c.562G>A	p.Glu188Lys	missense	Exon 6 of 6	NP_001231512.1	O14948-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFEC	ENST00000265440.12	TSL:1 MANE Select	c.763G>A	p.Glu255Lys	missense	Exon 8 of 8	ENSP00000265440.7	O14948-1
	TFEC	ENST00000320239.11	TSL:1	c.676G>A	p.Glu226Lys	missense	Exon 7 of 7	ENSP00000318676.7	O14948-2
	TFEC	ENST00000871199.1		c.763G>A	p.Glu255Lys	missense	Exon 10 of 10	ENSP00000541258.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.0010	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.23
Sift	Uncertain	0.019	D
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.26
MutPred		0.31		Gain of ubiquitination at E255 (P = 0.0039)
MVP		0.76
MPC		0.20
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.21
gMVP		0.32
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs1236936299; hg19: chr7-115580886;