Variant 1-42789895-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001354602.2(TMEM269):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000348 in 1,550,772 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: 𝑓 0.000098 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

TMEM269
NM_001354602.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.27

Variant links:

Genes affected

TMEM269 (HGNC:52381): (transmembrane protein 269) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM269 links:

LOC107984946 (HGNC:):

LOC107984946 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM269	NM_001354602.2 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	2/6	ENST00000637012.2	NP_001341531.2
LOC107984946	XR_007066036.1 linkuse as main transcript	n.89-1197A>T		intron_variant, non_coding_transcript_variant
LOC107984946	XR_001738020.2 linkuse as main transcript	n.86-1040A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TMEM269	ENST00000637012.2 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	2/6	5	NM_001354602.2	ENSP00000490213	P1
TMEM269	ENST00000536543.6 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	3/7	5		ENSP00000490716	P1
TMEM269	ENST00000421630.6 linkuse as main transcript	c.2T>A	p.Met1?	start_lost, NMD_transcript_variant	2/11	5		ENSP00000490287

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000133

AC:

AN:

149916

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000407

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000279

AC:

AN:

1398464

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

689744

show subpopulations

Gnomad4 AFR exome

AF:

0.000696

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.128T>A (p.M43K) alteration is located in exon 3 (coding exon 2) of the LOC100129924 gene. This alteration results from a T to A substitution at nucleotide position 128, causing the methionine (M) at amino acid position 43 to be replaced by a lysine (K). 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

Uncertain

0.45

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

DANN

Uncertain

0.98

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;T

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.81

PrimateAI

Benign

0.45

REVEL

Benign

0.21

GERP RS

4.5

Varity_R

0.50

gMVP

0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over