chr14-105528981-C-A

Variant names:

• chr14-105528981-C-A
• rs782177220
• NM_025268.4:c.147C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025268.4(TMEM121):​c.147C>A​(p.Asp49Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM121 NM_025268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025268.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM121	NM_025268.4	MANE Select	c.147C>A	p.Asp49Glu	missense	Exon 2 of 2	NP_079544.1	Q9BTD3
	TMEM121	NM_001331238.2		c.147C>A	p.Asp49Glu	missense	Exon 2 of 2	NP_001318167.1	Q9BTD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM121	ENST00000392519.7	TSL:1 MANE Select	c.147C>A	p.Asp49Glu	missense	Exon 2 of 2	ENSP00000376304.2	Q9BTD3
	TMEM121	ENST00000903730.1		c.147C>A	p.Asp49Glu	missense	Exon 2 of 2	ENSP00000573789.1
	TMEM121	ENST00000903731.1		c.147C>A	p.Asp49Glu	missense	Exon 2 of 2	ENSP00000573790.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242746 AF XY: 0.00000757

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459454 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726098

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000225 AC: 1 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111368

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.0038	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.51
Sift	Benign	0.066	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.82
MutPred		0.39		Gain of sheet (P = 0.0827)
MVP		0.35
MPC		2.3
ClinPred		0.57	D
GERP RS		2.0
PromoterAI		-0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.33
gMVP		0.97
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs782177220; hg19: chr14-105995318;