Genetic Variant TMEM161A:p.Ile455Thr (chr19-19120006-A-G) – 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_017814.3(TMEM161A):c.1364T>C(p.Ile455Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,441,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TMEM161A
NM_017814.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

Publications

0 publications found

Variant links:

Genes affected

TMEM161A (HGNC:26020): (transmembrane protein 161A) Involved in several processes, including cellular response to UV; regulation of response to DNA damage stimulus; and response to retinoic acid. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM161A links:

Genome browser will be placed here

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=0.07924169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM161A	NM_017814.3 link	c.1364T>C	p.Ile455Thr	missense_variant	Exon 12 of 12	ENST00000162044.14	NP_060284.1	Q9NX61-1
TMEM161A	NM_001411131.1 link	c.1289T>C	p.Ile430Thr	missense_variant	Exon 12 of 12		NP_001398060.1
TMEM161A	NM_001256766.3 link	c.1055T>C	p.Ile352Thr	missense_variant	Exon 10 of 10		NP_001243695.1	Q9NX61-2
TMEM161A	XM_047439023.1 link	c.1313T>C	p.Ile438Thr	missense_variant	Exon 12 of 12		XP_047294979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM161A	ENST00000162044.14 link	c.1364T>C	p.Ile455Thr	missense_variant	Exon 12 of 12	1	NM_017814.3	ENSP00000162044.7		Q9NX61-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000139

AC:

AN:

216460

AF XY:

0.0000171

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000182

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1441564

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

715324

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33140

American (AMR)

AF:

0.00

AC:

AN:

41680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25684

East Asian (EAS)

AF:

0.000103

AC:

AN:

38920

South Asian (SAS)

AF:

0.00

AC:

AN:

83262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5014

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102950

Other (OTH)

AF:

0.00

AC:

AN:

59544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1364T>C (p.I455T) alteration is located in exon 12 (coding exon 12) of the TMEM161A gene. This alteration results from a T to C substitution at nucleotide position 1364, causing the isoleucine (I) at amino acid position 455 to be replaced by a threonine (T). 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

0.27

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.035

.;T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.079

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.10

.;N;.

PhyloP100

7.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

1.4

N;N;.

REVEL

Benign

0.27

Sift

Benign

1.0

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.094

MutPred

0.59

.;Loss of stability (P = 0.007);.;

MVP

0.11

MPC

0.31

ClinPred

0.12

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.077

gMVP

0.47

Mutation Taster

=87/13

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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19-19120006-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over