19-19120028-G-C

Variant names:

• chr19-19120028-G-C
• rs151083836
• NM_017814.3:c.1342C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017814.3(TMEM161A):​c.1342C>G​(p.Arg448Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM161A NM_017814.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM161A	NM_017814.3	c.1342C>G	p.Arg448Gly	missense_variant	Exon 12 of 12	ENST00000162044.14	NP_060284.1
TMEM161A	NM_001411131.1	c.1267C>G	p.Arg423Gly	missense_variant	Exon 12 of 12		NP_001398060.1
TMEM161A	NM_001256766.3	c.1033C>G	p.Arg345Gly	missense_variant	Exon 10 of 10		NP_001243695.1
TMEM161A	XM_047439023.1	c.1291C>G	p.Arg431Gly	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	c.1342C>G	p.Arg448Gly	missense_variant	Exon 12 of 12	1	NM_017814.3	ENSP00000162044.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447772 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718932

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 42688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39170

South Asian (SAS) AF: 0.00 AC: 0 AN: 83950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5204

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106092

Other (OTH) AF: 0.00 AC: 0 AN: 59806

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	.;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	-0.0093
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	.;M;.
PhyloP100		2.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.5	D;D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.89
MutPred		0.90		.;Loss of methylation at R448 (P = 0.0131);.;
MVP		0.32
MPC		1.0
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.87
Mutation Taster		=23/77	disease causing

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: rs151083836; hg19: chr19-19230837;