chr6-130440594-T-C

Position:

• chr6-130440594-T-C

Variant summary

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

The NM_001258277.2(TMEM200A):​c.172T>C​(p.Tyr58His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM200A NM_001258277.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10

Genes affected

TMEM200A (HGNC:21075): (transmembrane protein 200A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM200A	NM_001258277.2	c.172T>C	p.Tyr58His	missense_variant	3/3	ENST00000296978.4	NP_001245206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM200A	ENST00000296978.4	c.172T>C	p.Tyr58His	missense_variant	3/3	1	NM_001258277.2	ENSP00000296978.3
TMEM200A	ENST00000392429.1	c.172T>C	p.Tyr58His	missense_variant	2/2	1		ENSP00000376224.1
TMEM200A	ENST00000545622.5	c.172T>C	p.Tyr58His	missense_variant	2/2	2		ENSP00000438928.1
TMEM200A	ENST00000617887.4	c.172T>C	p.Tyr58His	missense_variant	2/2	2		ENSP00000480294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.172T>C (p.Y58H) alteration is located in exon 2 (coding exon 1) of the TMEM200A gene. This alteration results from a T to C substitution at nucleotide position 172, causing the tyrosine (Y) at amino acid position 58 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;.;D;.
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	2.0	M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.33	T;.;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.89
MutPred		0.70		Loss of methylation at K54 (P = 0.0888);Loss of methylation at K54 (P = 0.0888);Loss of methylation at K54 (P = 0.0888);Loss of methylation at K54 (P = 0.0888);
MVP		0.18
MPC		0.71
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.69

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: rs1427778471; hg19: chr6-130761739;