6-44273106-G-A

Variant names:

• chr6-44273106-G-A
• rs542183426
• NM_001137560.2:c.176G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001137560.2(TMEM151B):​c.176G>A​(p.Arg59His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,514,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: TMEM151B NM_001137560.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

TMEM151B (HGNC:21315): (transmembrane protein 151B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000272442 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21795598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM151B	NM_001137560.2	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 3	ENST00000451188.7	NP_001131032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM151B	ENST00000451188.7	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 3	5	NM_001137560.2	ENSP00000393161.2
TMEM151B	ENST00000438774.2	c.176G>A	p.Arg59His	missense_variant	Exon 2 of 3	3		ENSP00000409337.2
ENSG00000272442	ENST00000505802.1	n.-89G>A		upstream_gene_variant		2		ENSP00000424257.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000587 AC: 8 AN: 1362580 Hom.: 0 Cov.: 32 AF XY: 0.00000300 AC XY: 2 AN XY: 665870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000583

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000284

Gnomad4 OTH exome AF: 0.0000530

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000257

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176G>A (p.R59H) alteration is located in exon 2 (coding exon 2) of the TMEM151B gene. This alteration results from a G to A substitution at nucleotide position 176, causing the arginine (R) at amino acid position 59 to be replaced by a histidine (H). 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	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.35
MutPred		0.54		Loss of MoRF binding (P = 0.0726);Loss of MoRF binding (P = 0.0726);
MVP		0.16
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs542183426; hg19: chr6-44240843;