rs786204662

Variant names:

• chr3-120644440-GCC-G
• rs786204662
• NM_000187.4:c.651_652delGG

Your query was ambiguous. Multiple possible variants found:

• chr3-120644440-GCC-G
• chr3-120644440-GCC-GC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000187.4(HGD):​c.651_652delGG​(p.Ala218GlnfsTer8) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGD NM_000187.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• alkaptonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-120644440-GCC-G is Pathogenic according to our data. Variant chr3-120644440-GCC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 643931.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000187.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGD	NM_000187.4	MANE Select	c.651_652delGG	p.Ala218GlnfsTer8	frameshift splice_region	Exon 10 of 14	NP_000178.2	Q93099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HGD	ENST00000283871.10	TSL:1 MANE Select	c.651_652delGG	p.Ala218GlnfsTer8	frameshift splice_region	Exon 10 of 14	ENSP00000283871.5	Q93099
	HGD	ENST00000898838.1		c.651_652delGG	p.Ala218GlnfsTer8	frameshift splice_region	Exon 10 of 15	ENSP00000568897.1
	HGD	ENST00000898833.1		c.651_652delGG	p.Ala218GlnfsTer8	frameshift splice_region	Exon 10 of 14	ENSP00000568892.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Alkaptonuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204662; hg19: chr3-120363287;