Genetic Variant ASPHD1:p.Pro199Leu (chr16-29901567-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_181718.4(ASPHD1):c.596C>T(p.Pro199Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,395,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P199R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ASPHD1
NM_181718.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

Publications

0 publications found

Variant links:

Genes affected

ASPHD1 (HGNC:27380): (aspartate beta-hydroxylase domain containing 1) Predicted to enable dioxygenase activity. Predicted to be involved in peptidyl-amino acid modification. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ASPHD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181718.4. 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
	ASPHD1	NM_181718.4	MANE Select	c.596C>T	p.Pro199Leu	missense	Exon 1 of 3	NP_859069.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASPHD1	ENST00000308748.10	TSL:1 MANE Select	c.596C>T	p.Pro199Leu	missense	Exon 1 of 3	ENSP00000311447.5	Q5U4P2
ASPHD1	ENST00000566693.1	TSL:1	n.596C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000456801.1	Q5U4P2
ASPHD1	ENST00000867089.1		c.596C>T	p.Pro199Leu	missense	Exon 1 of 2	ENSP00000537148.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000521

AC:

AN:

191880

AF XY:

0.00000957

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1395918

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31236

American (AMR)

AF:

0.00

AC:

AN:

33922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22092

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086644

Other (OTH)

AF:

0.00

AC:

AN:

57610

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

PhyloP100

7.3

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.93

Vest4

0.86

MutPred

0.61

Loss of disorder (P = 0.0157)

MVP

0.91

MPC

1.5

ClinPred

0.97

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.71

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over