Genetic Variant TMEM121:p.Ser310Phe (chr14-105529763-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025268.4(TMEM121):c.929C>T(p.Ser310Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 1,338,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TMEM121
NM_025268.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Publications

0 publications found

Variant links:

Genes affected

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

TMEM121 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10143107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM121	NM_025268.4 link	c.929C>T	p.Ser310Phe	missense_variant	Exon 2 of 2	ENST00000392519.7	NP_079544.1	Q9BTD3
TMEM121	NM_001331238.2 link	c.929C>T	p.Ser310Phe	missense_variant	Exon 2 of 2		NP_001318167.1	Q9BTD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM121	ENST00000392519.7 link	c.929C>T	p.Ser310Phe	missense_variant	Exon 2 of 2	1	NM_025268.4	ENSP00000376304.2		Q9BTD3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000224

AC:

AN:

1338498

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

659794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28624

American (AMR)

AF:

0.00

AC:

AN:

25168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22182

East Asian (EAS)

AF:

0.00

AC:

AN:

34390

South Asian (SAS)

AF:

0.00

AC:

AN:

71368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4858

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1062334

Other (OTH)

AF:

0.00

AC:

AN:

55796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.929C>T (p.S310F) alteration is located in exon 2 (coding exon 1) of the TMEM121 gene. This alteration results from a C to T substitution at nucleotide position 929, causing the serine (S) at amino acid position 310 to be replaced by a phenylalanine (F). 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

Benign

0.16

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.071

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.75

.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.9

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.049

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.011

B;B

Vest4

0.15

MutPred

0.18

Loss of phosphorylation at S310 (P = 0.0096);Loss of phosphorylation at S310 (P = 0.0096);

MVP

0.092

MPC

1.5

ClinPred

0.35

GERP RS

4.3

Varity_R

0.11

gMVP

0.38

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over