Variant 3-120628465-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000187.4(HGD):c.1253G>A(p.Cys418Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HGD
NM_000187.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86

Variant links:

Genes affected

HGD (HGNC:4892): (homogentisate 1,2-dioxygenase) This gene encodes the enzyme homogentisate 1,2 dioxygenase. This enzyme is involved in the catabolism of the amino acids tyrosine and phenylalanine. Mutations in this gene are the cause of the autosomal recessive metabolism disorder alkaptonuria.[provided by RefSeq, May 2010]

HGD links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28066254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4 link	c.1253G>A	p.Cys418Tyr	missense_variant	Exon 14 of 14	ENST00000283871.10	NP_000178.2	Q93099
HGD	XM_005247412.3 link	c.1028G>A	p.Cys343Tyr	missense_variant	Exon 12 of 12		XP_005247469.1
HGD	XM_017006277.3 link	c.830G>A	p.Cys277Tyr	missense_variant	Exon 14 of 14		XP_016861766.1	B3KW64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HGD	ENST00000283871.10 link	c.1253G>A	p.Cys418Tyr	missense_variant	Exon 14 of 14	1	NM_000187.4	ENSP00000283871.5	Q93099
HGD	ENST00000492108.5 link	n.*235G>A		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000419838.1	H7C5G7
HGD	ENST00000492108.5 link	n.*235G>A		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000419838.1	H7C5G7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1253G>A (p.C418Y) alteration is located in exon 14 (coding exon 14) of the HGD gene. This alteration results from a G to A substitution at nucleotide position 1253, causing the cysteine (C) at amino acid position 418 to be replaced by a tyrosine (Y). 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

0.14

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Uncertain

0.63

Eigen

Benign

-0.15

Eigen_PC

Benign

0.0084

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.28

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.73

REVEL

Uncertain

0.49

Sift

Benign

1.0

Sift4G

Benign

0.21

Polyphen

0.080

Vest4

0.34

MutPred

0.33

Loss of catalytic residue at L419 (P = 0.0278);

MVP

0.94

MPC

0.16

ClinPred

0.32

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.27

gMVP

0.68

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over