9-136116519-C-T

Position:

• chr9-136116519-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000418388.6(TMEM250):​c.382G>A​(p.Gly128Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM250 ENST00000418388.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

Genes affected

TMEM250 (HGNC:31009): (transmembrane protein 250) Predicted to enable GTPase activity and molecular adaptor activity. Involved in positive regulation of cell population proliferation and positive regulation of viral process. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM250	NM_152833.3	c.382G>A	p.Gly128Ser	missense_variant	2/2	ENST00000418388.6	NP_690046.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM250	ENST00000418388.6	c.382G>A	p.Gly128Ser	missense_variant	2/2	1	NM_152833.3	ENSP00000453019	P1
TMEM250	ENST00000557985.2	c.382G>A	p.Gly128Ser	missense_variant, NMD_transcript_variant	2/3	1		ENSP00000457272
TMEM250	ENST00000561457.2	c.382G>A	p.Gly128Ser	missense_variant	2/2	2		ENSP00000452750	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jul 13, 2021

The c.382G>A (p.A128T) alteration is located in exon 2 (coding exon 1) of the C9orf69 gene. This alteration results from a G to A substitution at nucleotide position 382, causing the alanine (A) at amino acid position 128 to be replaced by a threonine (T). 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	0.43
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.85	D;D
MutationTaster	Benign	0.97	D;D
PROVEAN	Pathogenic	-6.0	.;D
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.93
MVP		0.076
MPC		1.7
GERP RS		5.0
Varity_R		0.69
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: chr9-139008365;