3-44861946-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144638.3(TMEM42):c.22C>G(p.Pro8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,255,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

TMEM42
NM_144638.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.617

Variant links:

Genes affected

TMEM42 (HGNC:28444): (transmembrane protein 42) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM42 links:

MIR564 (HGNC:32820): (microRNA 564) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR564 links:

KIF15 (HGNC:17273): (kinesin family member 15) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

KIF15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04943329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM42	NM_144638.3 link	c.22C>G	p.Pro8Ala	missense_variant	Exon 1 of 3	ENST00000302392.5	NP_653239.1	Q69YG0
MIR564	NR_030290.1 link	n.59C>G		non_coding_transcript_exon_variant	Exon 1 of 1
KIF15	XR_007095708.1 link	n.4368-6545C>G		intron_variant	Intron 36 of 36
MIR564	unassigned_transcript_604	n.*25C>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM42	ENST00000302392.5 link	c.22C>G	p.Pro8Ala	missense_variant	Exon 1 of 3	1	NM_144638.3	ENSP00000306564.4	Q69YG0
TMEM42	ENST00000477126.1 link	n.43C>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
MIR564	ENST00000385049.1 link	n.59C>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
KIF15	ENST00000422209.1 link	n.*59+9152C>G		intron_variant	Intron 6 of 6	3		ENSP00000391205.1	H7BZT2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000159

AC:

AN:

1255466

Hom.:

Cov.:

AF XY:

0.00000327

AC XY:

AN XY:

611162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24552

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18692

East Asian (EAS)

AF:

0.00

AC:

AN:

27830

South Asian (SAS)

AF:

0.00

AC:

AN:

61350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4820

European-Non Finnish (NFE)

AF:

0.00000197

AC:

AN:

1015518

Other (OTH)

AF:

0.00

AC:

AN:

51338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.22C>G (p.P8A) alteration is located in exon 1 (coding exon 1) of the TMEM42 gene. This alteration results from a C to G substitution at nucleotide position 22, causing the proline (P) at amino acid position 8 to be replaced by an alanine (A). 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

0.047

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.4

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0046

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

M_CAP

Benign

0.024

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.080

REVEL

Benign

0.018

Sift

Benign

0.54

Sift4G

Benign

0.91

Polyphen

0.0

Vest4

0.089

MutPred

0.14

Loss of glycosylation at P8 (P = 0.0251);

MVP

0.030

MPC

0.26

ClinPred

0.029

GERP RS

0.022

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.024

gMVP

0.19

Mutation Taster

=99/1

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over