17-7436034-A-C

Variant names:

• chr17-7436034-A-C
• rs1180556370
• NM_178518.3:c.163A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178518.3(TMEM102):​c.163A>C​(p.Lys55Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,326 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: TMEM102 NM_178518.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.658

Genes affected

TMEM102 (HGNC:26722): (transmembrane protein 102) Involved in regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; response to cytokine; and signal transduction. Acts upstream of or within positive regulation of T cell migration and positive regulation of cell adhesion. Located in cell surface. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286007 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05596754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM102	NM_178518.3	c.163A>C	p.Lys55Gln	missense_variant	Exon 2 of 3	ENST00000323206.2	NP_848613.1
TMEM102	NM_001320444.1	c.163A>C	p.Lys55Gln	missense_variant	Exon 1 of 2		NP_001307373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM102	ENST00000323206.2	c.163A>C	p.Lys55Gln	missense_variant	Exon 2 of 3	1	NM_178518.3	ENSP00000315387.1
ENSG00000286007	ENST00000651314.1	n.*51A>C		non_coding_transcript_exon_variant	Exon 3 of 4			ENSP00000498964.1
ENSG00000286007	ENST00000651314.1	n.*51A>C		3_prime_UTR_variant	Exon 3 of 4			ENSP00000498964.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249634 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461326 Hom.: 1 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.163A>C (p.K55Q) alteration is located in exon 2 (coding exon 1) of the TMEM102 gene. This alteration results from a A to C substitution at nucleotide position 163, causing the lysine (K) at amino acid position 55 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	0.093
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.0038	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.53	D
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.031
Sift	Benign	0.72	T;T
Sift4G	Uncertain	0.026	D;D
Polyphen		0.0030	B;B
Vest4		0.17
MutPred		0.29		Loss of ubiquitination at K55 (P = 0.0081);Loss of ubiquitination at K55 (P = 0.0081);
MVP		0.28
ClinPred		0.051	T
GERP RS		-1.3
Varity_R		0.081
gMVP		0.25

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: rs1180556370; hg19: chr17-7339353;