rs7652072

Variant names:

• chr3-120652655-G-A
• rs7652072
• NM_000187.4:c.283-4C>T

Variant summary

Our verdict is Benign. The variant received -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, 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, 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HGD	NM_000187.4	c.283-4C>T		splice_region_variant, intron_variant	Intron 4 of 13	ENST00000283871.10	NP_000178.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HGD	ENST00000283871.10	c.283-4C>T		splice_region_variant, intron_variant	Intron 4 of 13	1	NM_000187.4	ENSP00000283871.5
HGD	ENST00000476082.2	c.160-4C>T		splice_region_variant, intron_variant	Intron 3 of 6	5		ENSP00000419560.2
HGD	ENST00000485313.5	n.391-4C>T		splice_region_variant, intron_variant	Intron 5 of 6	5
HGD	ENST00000488183.5	n.541-9C>T		intron_variant	Intron 5 of 5	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

GnomAD2 exomes AF: 0.00148 AC: 364 AN: 246396 AF XY: 0.00116

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 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

African (AFR) AF: 0.0160 AC: 535 AN: 33336

American (AMR) AF: 0.00116 AC: 52 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00284 AC: 16 AN: 5640

European-Non Finnish (NFE) AF: 0.000167 AC: 185 AN: 1106068

Other (OTH) AF: 0.00140 AC: 84 AN: 60128

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

African (AFR) AF: 0.0164 AC: 677 AN: 41374

American (AMR) AF: 0.00190 AC: 29 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67878

Other (OTH) AF: 0.00618 AC: 13 AN: 2102

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

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs7652072; hg19: chr3-120371502;