14-105529393-T-G

Position:

• chr14-105529393-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025268.4(TMEM121):​c.559T>G​(p.Cys187Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,391,590 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.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: TMEM121 NM_025268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

Genes affected

TMEM121 (HGNC:20511): (transmembrane protein 121) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM121	NM_025268.4	c.559T>G	p.Cys187Gly	missense_variant	2/2	ENST00000392519.7	NP_079544.1
TMEM121	NM_001331238.2	c.559T>G	p.Cys187Gly	missense_variant	2/2		NP_001318167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM121	ENST00000392519.7	c.559T>G	p.Cys187Gly	missense_variant	2/2	1	NM_025268.4	ENSP00000376304.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1391590 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 2 AN XY: 686720

Gnomad4 AFR exome AF: 0.00

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: 0.00000649

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.559T>G (p.C187G) alteration is located in exon 2 (coding exon 1) of the TMEM121 gene. This alteration results from a T to G substitution at nucleotide position 559, causing the cysteine (C) at amino acid position 187 to be replaced by a glycine (G). 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	0.48
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.62		Loss of stability (P = 0.0499);Loss of stability (P = 0.0499);
MVP		0.34
MPC		2.6
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.98

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: rs372023796; hg19: chr14-105995730;