1-29121548-A-C

Variant names:

• chr1-29121548-A-C
• rs760009447
• NM_001003682.4:c.281T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001003682.4(TMEM200B):​c.281T>G​(p.Met94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,508,372 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: TMEM200B NM_001003682.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.898
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008048385).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.281T>G	p.Met94Arg	missense	Exon 2 of 2	NP_001003682.1	Q69YZ2
	TMEM200B	NM_001171868.2		c.281T>G	p.Met94Arg	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.281T>G	p.Met94Arg	missense	Exon 2 of 2	ENSP00000428459.1	Q69YZ2
	TMEM200B	ENST00000420504.2	TSL:1	c.281T>G	p.Met94Arg	missense	Exon 2 of 2	ENSP00000428544.1	Q69YZ2
	TMEM200B	ENST00000870613.1		c.281T>G	p.Met94Arg	missense	Exon 3 of 3	ENSP00000540672.1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 151656 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00267

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00114 AC: 118 AN: 103874 AF XY: 0.00104

Gnomad AFR exome AF: 0.000668

Gnomad AMR exome AF: 0.000157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.000613

GnomAD4 exome AF: 0.00236 AC: 3201 AN: 1356608 Hom.: 5 Cov.: 31 AF XY: 0.00227 AC XY: 1520 AN XY: 669808

African (AFR) AF: 0.000283 AC: 8 AN: 28230

American (AMR) AF: 0.000233 AC: 7 AN: 30030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23750

East Asian (EAS) AF: 0.00 AC: 0 AN: 33550

South Asian (SAS) AF: 0.000536 AC: 41 AN: 76522

European-Finnish (FIN) AF: 0.00187 AC: 62 AN: 33090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5240

European-Non Finnish (NFE) AF: 0.00278 AC: 2970 AN: 1069628

Other (OTH) AF: 0.00200 AC: 113 AN: 56568

GnomAD4 genome AF: 0.00142 AC: 215 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74192

African (AFR) AF: 0.000555 AC: 23 AN: 41448

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4810

European-Finnish (FIN) AF: 0.00267 AC: 28 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00230 AC: 156 AN: 67852

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.00120

ExAC AF: 0.000352 AC: 18

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	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.5
DANN	Benign	0.52
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.90
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.30	N
REVEL	Benign	0.035
Sift	Benign	0.61	T
Sift4G	Uncertain	0.024	D
Polyphen		0.0050	B
Vest4		0.089
MVP		0.030
MPC		1.2
ClinPred		0.0014	T
GERP RS		0.34
Varity_R		0.14
gMVP		0.37
Mutation Taster		=99/1	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: rs760009447; hg19: chr1-29448060; COSMIC: COSV100549046; COSMIC: COSV100549046;