2-46480456-G-C

Variant names:

• chr2-46480456-G-C
• rs139055089
• ENST00000434431.2:c.169G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001424184.1(TMEM247):​c.169G>C​(p.Glu57Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,551,598 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: TMEM247 NM_001424184.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

Genes affected

TMEM247 (HGNC:42967): (transmembrane protein 247) Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000284608 (HGNC:):

LINC02583 (HGNC:53812): (long intergenic non-protein coding RNA 2583)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060884953).
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM247	NM_001424184.1	c.169G>C	p.Glu57Gln	missense_variant	Exon 2 of 3		NP_001411113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM247	ENST00000434431.2	c.169G>C	p.Glu57Gln	missense_variant	Exon 2 of 3	5		ENSP00000388684.1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00209 AC: 326 AN: 156224 AF XY: 0.00194

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000717

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00268 AC: 3749 AN: 1399288 Hom.: 7 Cov.: 32 AF XY: 0.00261 AC XY: 1803 AN XY: 690152

African (AFR) AF: 0.000886 AC: 28 AN: 31598

American (AMR) AF: 0.00392 AC: 140 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000480 AC: 38 AN: 79234

European-Finnish (FIN) AF: 0.000549 AC: 27 AN: 49166

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5698

European-Non Finnish (NFE) AF: 0.00308 AC: 3319 AN: 1078964

Other (OTH) AF: 0.00314 AC: 182 AN: 58008

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74482

African (AFR) AF: 0.00115 AC: 48 AN: 41574

American (AMR) AF: 0.00666 AC: 102 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68022

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00306 Hom.: 1

Bravo AF: 0.00281

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00311 AC: 12

ExAC AF: 0.000861 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>C (p.E57Q) alteration is located in exon 2 (coding exon 2) of the TMEM247 gene. This alteration results from a G to C substitution at nucleotide position 169, causing the glutamic acid (E) at amino acid position 57 to be replaced by a glutamine (Q). 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	0.19
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.0074
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.0
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.72	P
MVP		0.048
ClinPred		0.084	T
GERP RS		4.8
Varity_R		0.14

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

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Other links and lift over

dbSNP: rs139055089; hg19: chr2-46707595;