14-105529561-A-T

Variant names:

• chr14-105529561-A-T
• rs1555444300
• NM_025268.4:c.727A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025268.4(TMEM121):​c.727A>T​(p.Ser243Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,398,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: TMEM121 NM_025268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3847583).

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.727A>T	p.Ser243Cys	missense	Exon 2 of 2	NP_079544.1	Q9BTD3
	TMEM121	NM_001331238.2		c.727A>T	p.Ser243Cys	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.727A>T	p.Ser243Cys	missense	Exon 2 of 2	ENSP00000376304.2	Q9BTD3
	TMEM121	ENST00000903730.1		c.727A>T	p.Ser243Cys	missense	Exon 2 of 2	ENSP00000573789.1
	TMEM121	ENST00000903731.1		c.727A>T	p.Ser243Cys	missense	Exon 2 of 2	ENSP00000573790.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000643 AC: 1 AN: 155432 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000386

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: 0.00

GnomAD4 exome AF: 0.00000644 AC: 9 AN: 1398490 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691176

African (AFR) AF: 0.00 AC: 0 AN: 32078

American (AMR) AF: 0.0000270 AC: 1 AN: 36994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25222

East Asian (EAS) AF: 0.00 AC: 0 AN: 36396

South Asian (SAS) AF: 0.00 AC: 0 AN: 79928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000737 AC: 8 AN: 1085404

Other (OTH) AF: 0.00 AC: 0 AN: 58358

GnomAD4 genome Cov.: 34

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	Benign	0.26
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Uncertain	0.97
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.49
Sift	Benign	0.088	T
Sift4G	Benign	0.089	T
Polyphen		0.68	P
Vest4		0.51
MutPred		0.36		Loss of catalytic residue at S243 (P = 0.0135)
MVP		0.11
MPC		2.3
ClinPred		0.37	T
GERP RS		1.9
Varity_R		0.12
gMVP		0.89
Mutation Taster		=71/29	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: rs1555444300; hg19: chr14-105995898;