Genetic Variant NM_001330449.2:c.727C>A (chr16-2528245-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001330449.2(AMDHD2):c.727C>A(p.Arg243Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,692 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. R243C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

AMDHD2
NM_001330449.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.69

Publications

1 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330449.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMDHD2	NM_001330449.2	MANE Select	c.727C>A	p.Arg243Ser	missense	Exon 7 of 11	NP_001317378.1	Q9Y303-1
AMDHD2	NM_001145815.2		c.727C>A	p.Arg243Ser	missense	Exon 7 of 11	NP_001139287.1	Q9Y303-3
AMDHD2	NM_015944.4		c.727C>A	p.Arg243Ser	missense	Exon 7 of 10	NP_057028.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AMDHD2	ENST00000293971.11	TSL:1 MANE Select	c.727C>A	p.Arg243Ser	missense	Exon 7 of 11	ENSP00000293971.6	Q9Y303-1
AMDHD2	ENST00000302956.8	TSL:1	c.727C>A	p.Arg243Ser	missense	Exon 7 of 10	ENSP00000307481.4	Q9Y303-2
AMDHD2	ENST00000413459.7	TSL:2	c.727C>A	p.Arg243Ser	missense	Exon 7 of 11	ENSP00000391596.3	Q9Y303-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248032

AF XY:

0.00000743

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:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459692

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000225

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

5.3

PhyloP100

3.7

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.64

Loss of helix (P = 0.0068)

MVP

0.87

MPC

1.8

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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