19-19121546-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017814.3(TMEM161A):​c.779C>G​(p.Ser260Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. S260L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27391487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM161A	NM_017814.3	c.779C>G	p.Ser260Trp	missense_variant	Exon 8 of 12	ENST00000162044.14	NP_060284.1
TMEM161A	NM_001411131.1	c.704C>G	p.Ser235Trp	missense_variant	Exon 8 of 12		NP_001398060.1
TMEM161A	NM_001256766.3	c.470C>G	p.Ser157Trp	missense_variant	Exon 6 of 10		NP_001243695.1
TMEM161A	XM_047439023.1	c.728C>G	p.Ser243Trp	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>G	p.Ser260Trp	missense_variant	Exon 8 of 12	1	NM_017814.3	ENSP00000162044.7

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 11 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461694 Hom.: 0 Cov.: 34 AF XY: 0.0000784 AC XY: 57 AN XY: 727142

African (AFR) AF: 0.0000299 AC: 1 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: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111962

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74282

African (AFR) AF: 0.0000483 AC: 2 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.779C>G (p.S260W) alteration is located in exon 8 (coding exon 8) of the TMEM161A gene. This alteration results from a C to G substitution at nucleotide position 779, causing the serine (S) at amino acid position 260 to be replaced by a tryptophan (W). 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	0.24
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;T;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.6	.;L;.;.;.
PhyloP100		3.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D;D;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.17	T;T;.;.;.
Sift4G	Uncertain	0.012	D;D;D;D;.
Polyphen		0.98	.;D;.;.;.
Vest4		0.56
MVP		0.36
MPC		0.96
ClinPred		0.61	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.34
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;