12-47965942-A-T

Variant names:

• chr12-47965942-A-T
• rs1318551876
• NM_001143842.2:c.356A>T

Variant summary

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

The NM_001143842.2(TMEM106C):​c.356A>T​(p.Lys119Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM106C NM_001143842.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

TMEM106C (HGNC:28775): (transmembrane protein 106C) Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106C	NM_001143842.2	c.356A>T	p.Lys119Ile	missense_variant	Exon 4 of 8	ENST00000429772.7	NP_001137314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106C	ENST00000429772.7	c.356A>T	p.Lys119Ile	missense_variant	Exon 4 of 8	2	NM_001143842.2	ENSP00000400471.2
TMEM106C	ENST00000552546.5	c.143A>T	p.Lys48Ile	missense_variant	Exon 3 of 7	4		ENSP00000448268.1
TMEM106C	ENST00000548640.5	c.143A>T	p.Lys48Ile	missense_variant	Exon 3 of 7	3		ENSP00000447254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.356A>T (p.K119I) alteration is located in exon 4 (coding exon 3) of the TMEM106C gene. This alteration results from a A to T substitution at nucleotide position 356, causing the lysine (K) at amino acid position 119 to be replaced by an isoleucine (I). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	.;T;.;.;T;.;.;.
Eigen	Benign	0.050
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;.;D;.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M;.;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;.;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		0.87	P;P;.;P;P;.;P;.
Vest4		0.53
MutPred		0.58		Loss of ubiquitination at K119 (P = 0.0255);Loss of ubiquitination at K119 (P = 0.0255);.;Loss of ubiquitination at K119 (P = 0.0255);Loss of ubiquitination at K119 (P = 0.0255);Loss of ubiquitination at K119 (P = 0.0255);Loss of ubiquitination at K119 (P = 0.0255);.;
MVP		0.42
MPC		0.99
ClinPred		0.88	D
GERP RS		1.9
Varity_R		0.42
gMVP		0.40

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: rs1318551876; hg19: chr12-48359725;