1-29121496-G-C

Variant names:

• chr1-29121496-G-C
• rs1237496738
• NM_001003682.4:c.333C>G

Variant summary

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

The NM_001003682.4(TMEM200B):​c.333C>G​(p.His111Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000722 in 1,522,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: TMEM200B NM_001003682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.150
• Publications: 0 publications found

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

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=0.17000577).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003682.4. 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
	TMEM200B	NM_001003682.4	MANE Select	c.333C>G	p.His111Gln	missense	Exon 2 of 2	NP_001003682.1	Q69YZ2
	TMEM200B	NM_001171868.2		c.333C>G	p.His111Gln	missense	Exon 2 of 2	NP_001165339.1	Q69YZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM200B	ENST00000521452.2	TSL:1 MANE Select	c.333C>G	p.His111Gln	missense	Exon 2 of 2	ENSP00000428459.1	Q69YZ2
	TMEM200B	ENST00000420504.2	TSL:1	c.333C>G	p.His111Gln	missense	Exon 2 of 2	ENSP00000428544.1	Q69YZ2
	TMEM200B	ENST00000870613.1		c.333C>G	p.His111Gln	missense	Exon 3 of 3	ENSP00000540672.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151792 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000414 AC: 5 AN: 120662 AF XY: 0.0000603

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000405

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000225

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000656 AC: 9 AN: 1371034 Hom.: 0 Cov.: 31 AF XY: 0.00000740 AC XY: 5 AN XY: 675546

African (AFR) AF: 0.00 AC: 0 AN: 30876

American (AMR) AF: 0.00 AC: 0 AN: 33888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24560

East Asian (EAS) AF: 0.000170 AC: 6 AN: 35264

South Asian (SAS) AF: 0.00 AC: 0 AN: 78476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5486

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1072006

Other (OTH) AF: 0.0000175 AC: 1 AN: 57226

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151896 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74220

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.15
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.28
Sift	Benign	0.030	D
Sift4G	Uncertain	0.030	D
Polyphen		0.67	P
Vest4		0.15
MutPred		0.41		Gain of helix (P = 0.062)
MVP		0.099
MPC		1.1
ClinPred		0.090	T
GERP RS		2.7
Varity_R		0.091
gMVP		0.49
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1237496738; hg19: chr1-29448008;