Genetic Variant NM_024684.4:c.49A>C (chr11-77842545-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024684.4(AAMDC):c.49A>C(p.Lys17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. K17E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AAMDC
NM_024684.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.29

Publications

0 publications found

Variant links:

Genes affected

AAMDC (HGNC:30205): (adipogenesis associated Mth938 domain containing) Predicted to be involved in positive regulation of fat cell differentiation. Predicted to act upstream of or within negative regulation of apoptotic process and positive regulation of transcription by RNA polymerase II. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AAMDC links:

ENSG00000254459 (HGNC:):

ENSG00000254459 links:

RSF1 (HGNC:18118): (remodeling and spacing factor 1) This gene encodes a nuclear protein that interacts with hepatitis B virus X protein (HBX) and facilitates transcription of hepatitis B virus genes by the HBX transcription activator, suggesting a role for this interaction in the virus life cycle. This protein also interacts with SNF2H protein to form the RSF chromatin-remodeling complex, where the SNF2H subunit functions as the nucleosome-dependent ATPase, and this protein as the histone chaperone. [provided by RefSeq, Sep 2011]

RSF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056988806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAMDC	NM_024684.4 link	c.49A>C	p.Lys17Gln	missense_variant	Exon 2 of 4	ENST00000393427.7	NP_078960.1	Q9H7C9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAMDC	ENST00000393427.7 link	c.49A>C	p.Lys17Gln	missense_variant	Exon 2 of 4	1	NM_024684.4	ENSP00000377078.2		Q9H7C9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.048

.;T;T;.;.;.;T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.69

T;.;T;T;.;T;T;T;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.057

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.99

L;L;L;.;.;.;.;.;.

PhyloP100

1.3

PrimateAI

Benign

0.38

PROVEAN

Benign

0.13

N;N;N;N;N;.;N;N;N

REVEL

Benign

0.025

Sift

Benign

0.65

T;T;T;T;T;.;T;T;T

Sift4G

Benign

0.43

T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;.;.;.;.;.

Vest4

0.082

MutPred

0.33

Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);Loss of methylation at K17 (P = 0.0277);.;

MVP

0.11

MPC

0.019

ClinPred

0.069

GERP RS

2.6

Varity_R

0.18

gMVP

0.41

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over