chr12-49089916-A-T
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The NM_021044.4(DHH):c.1134T>A(p.Thr378=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,592,258 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00030 ( 2 hom. )
Consequence
DHH
NM_021044.4 synonymous
NM_021044.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -5.61
Genes affected
DHH (HGNC:2865): (desert hedgehog signaling molecule) This gene encodes a member of the hedgehog family. The hedgehog gene family encodes signaling molecules that play an important role in regulating morphogenesis. This protein is predicted to be made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the organism. Defects in this protein have been associated with partial gonadal dysgenesis (PGD) accompanied by minifascicular polyneuropathy. This protein may be involved in both male gonadal differentiation and perineurial development. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 12-49089916-A-T is Benign according to our data. Variant chr12-49089916-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 309098.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr12-49089916-A-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-5.61 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000525 (80/152380) while in subpopulation AMR AF= 0.00294 (45/15310). AF 95% confidence interval is 0.00226. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DHH | NM_021044.4 | c.1134T>A | p.Thr378= | synonymous_variant | 3/3 | ENST00000649637.2 | |
| DHH | XM_017019380.2 | c.993T>A | p.Thr331= | synonymous_variant | 3/3 | ||
| DHH | XM_017019381.2 | c.792T>A | p.Thr264= | synonymous_variant | 3/3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DHH | ENST00000649637.2 | c.1134T>A | p.Thr378= | synonymous_variant | 3/3 | NM_021044.4 | P1 |
Frequencies
GnomAD3 genomes 0.000532 AC: 81AN: 152262Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000482 AC: 100AN: 207294Hom.: 1 AF XY: 0.000487 AC XY: 55AN XY: 112988
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GnomAD4 exome AF: 0.000304 AC: 438AN: 1439878Hom.: 2 Cov.: 31 AF XY: 0.000291 AC XY: 208AN XY: 714286
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GnomAD4 genome 0.000525 AC: 80AN: 152380Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47AN XY: 74516
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
46,XY sex reversal 7 Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 03, 2023 | - - |
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at