19-19121038-A-G

Variant names:

• chr19-19121038-A-G
• rs1663293396
• NM_017814.3:c.1043T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017814.3(TMEM161A):​c.1043T>C​(p.Leu348Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,958 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. L348Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM161A NM_017814.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.47
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM161A	NM_017814.3	c.1043T>C	p.Leu348Pro	missense_variant	Exon 10 of 12	ENST00000162044.14	NP_060284.1
TMEM161A	NM_001411131.1	c.968T>C	p.Leu323Pro	missense_variant	Exon 10 of 12		NP_001398060.1
TMEM161A	NM_001256766.3	c.734T>C	p.Leu245Pro	missense_variant	Exon 8 of 10		NP_001243695.1
TMEM161A	XM_047439023.1	c.992T>C	p.Leu331Pro	missense_variant	Exon 10 of 12		XP_047294979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM161A	ENST00000162044.14	c.1043T>C	p.Leu348Pro	missense_variant	Exon 10 of 12	1	NM_017814.3	ENSP00000162044.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458958 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725474

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110944

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.2	.;M;.;.
PhyloP100		8.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.99	.;D;.;.
Vest4		0.71
MutPred		0.79		.;Gain of disorder (P = 0.0103);.;.;
MVP		0.42
MPC		1.1
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.86
Mutation Taster		=20/80	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: rs1663293396; hg19: chr19-19231847;