22-17119485-G-A

Variant names:

• chr22-17119485-G-A
• rs138179417
• NM_031890.4:c.1643C>T

Variant summary

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

The NM_031890.4(TMEM121B):​c.1643C>T​(p.Pro548Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. P548H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM121B NM_031890.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14883348).

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.1643C>T	p.Pro548Leu	missense	Exon 1 of 1	NP_114096.1	Q9BXQ6-1
	TMEM121B	NM_001163079.2		c.578C>T	p.Pro193Leu	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.1643C>T	p.Pro548Leu	missense	Exon 1 of 1	ENSP00000329318.3	Q9BXQ6-1
	TMEM121B	ENST00000399875.1	TSL:2	c.578C>T	p.Pro193Leu	missense	Exon 2 of 2	ENSP00000382764.1	Q9BXQ6-2
	LINC01664	ENST00000846293.1		n.-34G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449536 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 720022

African (AFR) AF: 0.00 AC: 0 AN: 33146

American (AMR) AF: 0.00 AC: 0 AN: 43328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 38988

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106374

Other (OTH) AF: 0.00 AC: 0 AN: 59876

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.056
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.027	D
Polyphen		0.13	B
Vest4		0.27
MutPred		0.19		Loss of relative solvent accessibility (P = 0.008)
MVP		0.21
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.084
gMVP		0.22
Mutation Taster		=92/8	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: rs138179417; hg19: chr22-17600375;