9-101476334-G-C

Variant names:

• chr9-101476334-G-C
• NM_032342.3:c.759C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032342.3(PGAP4):​c.759C>G​(p.His253Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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: PGAP4 NM_032342.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

Genes affected

PGAP4 (HGNC:28180): (post-GPI attachment to proteins GalNAc transferase 4) Enables glycosyltransferase activity. Involved in GPI anchor biosynthetic process. Located in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM246-AS1 (HGNC:51191): (TMEM246 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11589283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP4	NM_032342.3	c.759C>G	p.His253Gln	missense_variant	Exon 2 of 2	ENST00000374848.8	NP_115718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP4	ENST00000374848.8	c.759C>G	p.His253Gln	missense_variant	Exon 2 of 2	1	NM_032342.3	ENSP00000363981.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.759C>G (p.H253Q) alteration is located in exon 2 (coding exon 1) of the TMEM246 gene. This alteration results from a C to G substitution at nucleotide position 759, causing the histidine (H) at amino acid position 253 to be replaced by a glutamine (Q). 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	Benign	0.30
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.042	T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	.;.;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.058	B;B;B
Vest4		0.16
MutPred		0.22		Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP		0.10
MPC		0.42
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.074
gMVP		0.71

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: chr9-104238616;