7-115940912-C-G

Variant names:

• chr7-115940912-C-G
• rs764957936
• NM_012252.4:c.683G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012252.4(TFEC):​c.683G>C​(p.Arg228Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,580,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TFEC NM_012252.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

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.683G>C	p.Arg228Pro	missense	Exon 8 of 8	NP_036384.1	O14948-1
	TFEC	NM_001018058.3		c.596G>C	p.Arg199Pro	missense	Exon 7 of 7	NP_001018068.1	O14948-2
	TFEC	NM_001244583.2		c.482G>C	p.Arg161Pro	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.683G>C	p.Arg228Pro	missense	Exon 8 of 8	ENSP00000265440.7	O14948-1
	TFEC	ENST00000320239.11	TSL:1	c.596G>C	p.Arg199Pro	missense	Exon 7 of 7	ENSP00000318676.7	O14948-2
	TFEC	ENST00000871199.1		c.683G>C	p.Arg228Pro	missense	Exon 10 of 10	ENSP00000541258.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428874 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 706382

African (AFR) AF: 0.00 AC: 0 AN: 32130

American (AMR) AF: 0.00 AC: 0 AN: 39946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24786

East Asian (EAS) AF: 0.00 AC: 0 AN: 39186

South Asian (SAS) AF: 0.00 AC: 0 AN: 82400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1093128

Other (OTH) AF: 0.00 AC: 0 AN: 58808

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.56		Loss of catalytic residue at R228 (P = 0.012)
MVP		0.77
MPC		0.31
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.91
gMVP		0.78
Mutation Taster		=57/43	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: rs764957936; hg19: chr7-115580966;