Genetic Variant ASPHD1:p.Ala76Thr (chr16-29901197-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181718.4(ASPHD1):c.226G>A(p.Ala76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A76D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ASPHD1
NM_181718.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20029885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPHD1	NM_181718.4 link	c.226G>A	p.Ala76Thr	missense_variant	Exon 1 of 3	ENST00000308748.10	NP_859069.2	Q5U4P2
ASPHD1	XM_017023107.2 link	c.127+99G>A		intron_variant	Intron 1 of 3		XP_016878596.1
ASPHD1	XR_007064864.1 link	n.710G>A		non_coding_transcript_exon_variant	Exon 1 of 4
ASPHD1	XR_007064865.1 link	n.710G>A		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPHD1	ENST00000308748.10 link	c.226G>A	p.Ala76Thr	missense_variant	Exon 1 of 3	1	NM_181718.4	ENSP00000311447.5		Q5U4P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249652

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135208

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000603

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226G>A (p.A76T) alteration is located in exon 1 (coding exon 1) of the ASPHD1 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the alanine (A) at amino acid position 76 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.10

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.014

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.090

REVEL

Benign

0.072

Sift

Uncertain

0.0040

Sift4G

Benign

0.092

Polyphen

0.18

Vest4

0.21

MutPred

0.38

Loss of helix (P = 0.0123);

MVP

0.73

MPC

0.61

ClinPred

0.45

GERP RS

4.0

Varity_R

0.13

gMVP

0.067

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over