Variant chr16-2521089-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000293971.11(AMDHD2):c.326C>T(p.Thr109Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AMDHD2
ENST00000293971.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

Variant links:

Genes affected

AMDHD2 (HGNC:24262): (amidohydrolase domain containing 2) Enables N-acetylglucosamine-6-phosphate deacetylase activity. Predicted to be involved in N-acetylglucosamine catabolic process. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

AMDHD2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMDHD2	NM_001330449.2 linkuse as main transcript	c.326C>T	p.Thr109Ile	missense_variant	3/11	ENST00000293971.11	NP_001317378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMDHD2	ENST00000293971.11 linkuse as main transcript	c.326C>T	p.Thr109Ile	missense_variant	3/11	1	NM_001330449.2	ENSP00000293971	P1	Q9Y303-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

246906

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133468

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000555

Gnomad SAS 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:

6.89e-7

AC:

AN:

1451668

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720622

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:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.326C>T (p.T109I) alteration is located in exon 3 (coding exon 3) of the AMDHD2 gene. This alteration results from a C to T substitution at nucleotide position 326, causing the threonine (T) at amino acid position 109 to be replaced by an isoleucine (I). 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

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;D;.;.;.;.;T;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D;D;D;D;D

M_CAP

Benign

0.082

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

5.2

.;H;H;H;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.0

D;D;D;D;.;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

D;D;D;D;.;T;T;D

Sift4G

Pathogenic

0.0

D;D;D;D;.;D;D;D

Polyphen

1.0

.;D;D;D;.;.;.;.

Vest4

0.96, 0.93, 0.92

MutPred

0.86

.;Loss of catalytic residue at T109 (P = 0.0487);Loss of catalytic residue at T109 (P = 0.0487);Loss of catalytic residue at T109 (P = 0.0487);Loss of catalytic residue at T109 (P = 0.0487);Loss of catalytic residue at T109 (P = 0.0487);Loss of catalytic residue at T109 (P = 0.0487);Loss of catalytic residue at T109 (P = 0.0487);

MVP

0.47

MPC

1.8

ClinPred

1.0

GERP RS

5.3

Varity_R

0.96

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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