chr19-19121546-G-A

Variant names:

• chr19-19121546-G-A
• rs148244636
• NM_017814.3:c.779C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017814.3(TMEM161A):​c.779C>T​(p.Ser260Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S260W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TMEM161A NM_017814.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02
• Publications: 3 publications found

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]

ACMG classification

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=0.15568247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM161A	NM_017814.3	c.779C>T	p.Ser260Leu	missense_variant	Exon 8 of 12	ENST00000162044.14	NP_060284.1
TMEM161A	NM_001411131.1	c.704C>T	p.Ser235Leu	missense_variant	Exon 8 of 12		NP_001398060.1
TMEM161A	NM_001256766.3	c.470C>T	p.Ser157Leu	missense_variant	Exon 6 of 10		NP_001243695.1
TMEM161A	XM_047439023.1	c.728C>T	p.Ser243Leu	missense_variant	Exon 8 of 12		XP_047294979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM161A	ENST00000162044.14	c.779C>T	p.Ser260Leu	missense_variant	Exon 8 of 12	1	NM_017814.3	ENSP00000162044.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250784 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461694 Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111962

Other (OTH) AF: 0.0000662 AC: 4 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.779C>T (p.S260L) alteration is located in exon 8 (coding exon 8) of the TMEM161A gene. This alteration results from a C to T substitution at nucleotide position 779, causing the serine (S) at amino acid position 260 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	.;T;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	.;L;.;.;.
PhyloP100		3.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.2	N;N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.58	T;T;.;.;.
Sift4G	Uncertain	0.050	T;T;T;T;.
Polyphen		0.20	.;B;.;.;.
Vest4		0.38
MVP		0.25
MPC		0.29
ClinPred		0.077	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.23
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs148244636; hg19: chr19-19232355; COSMIC: COSV50777219; COSMIC: COSV50777219;