22-17119719-C-A

Variant names:

• chr22-17119719-C-A
• rs777950085
• NM_031890.4:c.1409G>T

Variant summary

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

The NM_031890.4(TMEM121B):​c.1409G>T​(p.Arg470Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,390,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R470H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TMEM121B NM_031890.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.27
• Publications: 0 publications found

Genes affected

TMEM121B (HGNC:1844): (transmembrane protein 121B)

LINC01664 (HGNC:52452): (long intergenic non-protein coding RNA 1664)

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=0.4138927).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031890.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM121B	NM_031890.4	MANE Select	c.1409G>T	p.Arg470Leu	missense	Exon 1 of 1	NP_114096.1	Q9BXQ6-1
	TMEM121B	NM_001163079.2		c.344G>T	p.Arg115Leu	missense	Exon 2 of 2	NP_001156551.1	Q9BXQ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM121B	ENST00000331437.4	TSL:6 MANE Select	c.1409G>T	p.Arg470Leu	missense	Exon 1 of 1	ENSP00000329318.3	Q9BXQ6-1
	TMEM121B	ENST00000399875.1	TSL:2	c.344G>T	p.Arg115Leu	missense	Exon 2 of 2	ENSP00000382764.1	Q9BXQ6-2
	LINC01664	ENST00000846293.1		n.201C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1390122 Hom.: 0 Cov.: 36 AF XY: 0.0000116 AC XY: 8 AN XY: 686710

African (AFR) AF: 0.00 AC: 0 AN: 31960

American (AMR) AF: 0.00 AC: 0 AN: 36012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36424

South Asian (SAS) AF: 0.00 AC: 0 AN: 80028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1082856

Other (OTH) AF: 0.0000172 AC: 1 AN: 58132

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.60	T
PhyloP100		4.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.46		Loss of disorder (P = 0.0883)
MVP		0.38
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.56
gMVP		0.65
Mutation Taster		=53/47	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: rs777950085; hg19: chr22-17600609;