17-82418418-C-T

Position:

• chr17-82418418-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330542.2(HEXD):​c.-374C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,478,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HEXD NM_001330542.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.11

Genes affected

HEXD (HGNC:26307): (hexosaminidase D) Enables beta-N-acetylhexosaminidase activity. Predicted to be involved in carbohydrate metabolic process. Located in extracellular vesicle. [provided by Alliance of Genome Resources, Apr 2022]

OGFOD3 (HGNC:26174): (2-oxoglutarate and iron dependent oxygenase domain containing 3) Predicted to enable several functions, including L-ascorbic acid binding activity; dioxygenase activity; and iron ion binding activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

OGFOD3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022119284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXD	NM_001330542.2	c.-374C>T		5_prime_UTR_premature_start_codon_gain_variant	1/13	ENST00000327949.15	NP_001317471.1
OGFOD3	NM_024648.3	c.68G>A	p.Arg23Gln	missense_variant	1/9	ENST00000313056.10	NP_078924.1
HEXD	NM_001330542.2	c.-374C>T		5_prime_UTR_variant	1/13	ENST00000327949.15	NP_001317471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXD	ENST00000327949	c.-374C>T		5_prime_UTR_premature_start_codon_gain_variant	1/13	1	NM_001330542.2	ENSP00000332634.9
OGFOD3	ENST00000313056.10	c.68G>A	p.Arg23Gln	missense_variant	1/9	2	NM_024648.3	ENSP00000320116.5
HEXD	ENST00000327949	c.-374C>T		5_prime_UTR_variant	1/13	1	NM_001330542.2	ENSP00000332634.9

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 151818 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000564 AC: 5 AN: 88612 Hom.: 0 AF XY: 0.0000997 AC XY: 5 AN XY: 50166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 31 AN: 1326944 Hom.: 0 Cov.: 30 AF XY: 0.0000214 AC XY: 14 AN XY: 654740

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000570

Gnomad4 OTH exome AF: 0.0000909

GnomAD4 genome AF: 0.000204 AC: 31 AN: 151926 Hom.: 0 Cov.: 30 AF XY: 0.000215 AC XY: 16 AN XY: 74248

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000276

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 10, 2024

The c.68G>A (p.R23Q) alteration is located in exon 1 (coding exon 1) of the OGFOD3 gene. This alteration results from a G to A substitution at nucleotide position 68, causing the arginine (R) at amino acid position 23 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	0.092
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.9
DANN	Benign	0.97
DEOGEN2	Benign	0.00023	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.0080
Sift	Benign	0.53	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0010	B;B
Vest4		0.071
MutPred		0.17		Gain of glycosylation at S24 (P = 0.0656);Gain of glycosylation at S24 (P = 0.0656);
MVP		0.040
MPC		0.88
ClinPred		0.029	T
GERP RS		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs527949734; hg19: chr17-80376294;