Genetic Variant TMEM161A:p.Arg448Cys (chr19-19120028-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_017814.3(TMEM161A):c.1342C>T(p.Arg448Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,599,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TMEM161A
NM_017814.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

Publications

3 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 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM161A	NM_017814.3 link	c.1342C>T	p.Arg448Cys	missense_variant	Exon 12 of 12	ENST00000162044.14	NP_060284.1	Q9NX61-1
TMEM161A	NM_001411131.1 link	c.1267C>T	p.Arg423Cys	missense_variant	Exon 12 of 12		NP_001398060.1
TMEM161A	NM_001256766.3 link	c.1033C>T	p.Arg345Cys	missense_variant	Exon 10 of 10		NP_001243695.1	Q9NX61-2
TMEM161A	XM_047439023.1 link	c.1291C>T	p.Arg431Cys	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.1342C>T	p.Arg448Cys	missense_variant	Exon 12 of 12	1	NM_017814.3	ENSP00000162044.7		Q9NX61-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000891

AC:

AN:

224492

AF XY:

0.000115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000200

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

179

AN:

1447772

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

718932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33246

American (AMR)

AF:

0.00

AC:

AN:

42688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39170

South Asian (SAS)

AF:

0.00

AC:

AN:

83950

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5204

European-Non Finnish (NFE)

AF:

0.000159

AC:

176

AN:

1106092

Other (OTH)

AF:

0.0000334

AC:

AN:

59806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1342C>T (p.R448C) alteration is located in exon 12 (coding exon 12) of the TMEM161A gene. This alteration results from a C to T substitution at nucleotide position 1342, causing the arginine (R) at amino acid position 448 to be replaced by a cysteine (C). 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

0.33

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T;T

Eigen

Benign

0.14

Eigen_PC

Benign

-0.033

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.8

.;M;.

PhyloP100

2.9

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.3

D;D;.

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.82

MVP

0.32

MPC

1.0

ClinPred

0.95

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.71

gMVP

0.83

Mutation Taster

=43/57

disease causing

(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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19-19120028-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over