1-29121296-G-T

Variant names:

• chr1-29121296-G-T
• rs1309763643
• NM_001003682.4:c.533C>A

Variant summary

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

The NM_001003682.4(TMEM200B):​c.533C>A​(p.Pro178His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,452,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (1 hom.)
• Consequence: TMEM200B NM_001003682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

Genes affected

TMEM200B (HGNC:33785): (transmembrane protein 200B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.16942027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM200B	NM_001003682.4	c.533C>A	p.Pro178His	missense_variant	Exon 2 of 2	ENST00000521452.2	NP_001003682.1
TMEM200B	NM_001171868.2	c.533C>A	p.Pro178His	missense_variant	Exon 2 of 2		NP_001165339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM200B	ENST00000521452.2	c.533C>A	p.Pro178His	missense_variant	Exon 2 of 2	1	NM_001003682.4	ENSP00000428459.1
TMEM200B	ENST00000420504.2	c.533C>A	p.Pro178His	missense_variant	Exon 2 of 2	1		ENSP00000428544.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1452008 Hom.: 1 Cov.: 31 AF XY: 0.00000970 AC XY: 7 AN XY: 721694

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000667

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533C>A (p.P178H) alteration is located in exon 2 (coding exon 1) of the TMEM200B gene. This alteration results from a C to A substitution at nucleotide position 533, causing the proline (P) at amino acid position 178 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	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.45	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.066
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.058	T;T
Polyphen		0.70	P;P
Vest4		0.23
MutPred		0.15		Loss of glycosylation at P178 (P = 0.0469);Loss of glycosylation at P178 (P = 0.0469);
MVP		0.15
MPC		2.1
ClinPred		0.45	T
GERP RS		2.5
Varity_R		0.11
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1309763643; hg19: chr1-29447808;