14-105529558-G-A

Position:

• chr14-105529558-G-A

Variant summary

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

The NM_025268.4(TMEM121):​c.724G>A​(p.Asp242Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMEM121 NM_025268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM121	NM_025268.4	c.724G>A	p.Asp242Asn	missense_variant	2/2	ENST00000392519.7	NP_079544.1
TMEM121	NM_001331238.2	c.724G>A	p.Asp242Asn	missense_variant	2/2		NP_001318167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM121	ENST00000392519.7	c.724G>A	p.Asp242Asn	missense_variant	2/2	1	NM_025268.4	ENSP00000376304.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397100 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690342

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: 9.22e-7

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

Mar 19, 2024

The c.724G>A (p.D242N) alteration is located in exon 2 (coding exon 1) of the TMEM121 gene. This alteration results from a G to A substitution at nucleotide position 724, causing the aspartic acid (D) at amino acid position 242 to be replaced by an asparagine (N). 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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.16
Sift	Benign	0.064	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.69
MutPred		0.35		Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);
MVP		0.081
MPC		2.1
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.25
gMVP		0.87

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: rs2084623962; hg19: chr14-105995895;