rs7652072

chr3-120652655-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000187.4(HGD):c.283-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,606,428 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (6 hom.)
• Consequence: HGD NM_000187.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001696
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-120652655-G-A is Benign according to our data. Variant chr3-120652655-G-A is described in ClinVar as [Benign]. Clinvar id is 784577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00489 (742/151710) while in subpopulation AFR AF= 0.0164 (677/41374). AF 95% confidence interval is 0.0153. There are 7 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGD	NM_000187.4	c.283-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000283871.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGD	ENST00000283871.10	c.283-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000187.4	P1
HGD	ENST00000476082.2	c.160-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
HGD	ENST00000485313.5	n.391-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5
HGD	ENST00000488183.5	n.541-9C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 741 AN: 151592 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00625

GnomAD3 exomes AF: 0.00148 AC: 364 AN: 246396 Hom.: 1 AF XY: 0.00116 AC XY: 154 AN XY: 133110

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000651 AC: 947 AN: 1454718 Hom.: 6 Cov.: 29 AF XY: 0.000599 AC XY: 434 AN XY: 724140

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.00140

GnomAD4 genome AF: 0.00489 AC: 742 AN: 151710 Hom.: 7 Cov.: 32 AF XY: 0.00447 AC XY: 331 AN XY: 74132

Gnomad4 AFR AF: 0.0164

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.00267 Hom.: 2

Bravo AF: 0.00531

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alkaptonuria Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	9.4
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.048
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

LitVar

Other links and lift over

dbSNP: rs7652072; hg19: chr3-120371502;