6-130440859-T-A

Position:

• chr6-130440859-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001258277.2(TMEM200A):​c.437T>A​(p.Ile146Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM200A NM_001258277.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM200A	NM_001258277.2	c.437T>A	p.Ile146Asn	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.437T>A	p.Ile146Asn	missense_variant	3/3	1	NM_001258277.2	ENSP00000296978.3
TMEM200A	ENST00000392429.1	c.437T>A	p.Ile146Asn	missense_variant	2/2	1		ENSP00000376224.1
TMEM200A	ENST00000545622.5	c.437T>A	p.Ile146Asn	missense_variant	2/2	2		ENSP00000438928.1
TMEM200A	ENST00000617887.4	c.437T>A	p.Ile146Asn	missense_variant	2/2	2		ENSP00000480294.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Dec 02, 2024

The c.437T>A (p.I146N) alteration is located in exon 2 (coding exon 1) of the TMEM200A gene. This alteration results from a T to A substitution at nucleotide position 437, causing the isoleucine (I) at amino acid position 146 to be replaced by an asparagine (N). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	.;.;D;.
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.3	M;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.8	D;.;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.89
MutPred		0.52		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.25
MPC		0.83
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-130762004;