chr1-27547398-G-A

Position:

chr1-27547398-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001371928.1(AHDC1):c.4718C>T(p.Ala1573Val) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,568,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

AHDC1
NM_001371928.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.13

Variant links:

Genes affected

AHDC1 (HGNC:25230): (AT-hook DNA binding motif containing 1) This gene encodes a protein containing two AT-hooks, which likely function in DNA binding. Mutations in this gene were found in individuals with Xia-Gibbs syndrome. [provided by RefSeq, Jun 2014]

AHDC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08254126).

BP6

Variant 1-27547398-G-A is Benign according to our data. Variant chr1-27547398-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2173017.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHDC1	NM_001371928.1 linkuse as main transcript	c.4718C>T	p.Ala1573Val	missense_variant	8/9	ENST00000673934.1	NP_001358857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHDC1	ENST00000673934.1 linkuse as main transcript	c.4718C>T	p.Ala1573Val	missense_variant	8/9		NM_001371928.1	ENSP00000501218	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000500

AC:

AN:

220220

Hom.:

AF XY:

0.0000422

AC XY:

AN XY:

118478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.000121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000499

Gnomad OTH exome

AF:

0.000192

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1416718

Hom.:

Cov.:

AF XY:

0.0000457

AC XY:

AN XY:

699594

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000253

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000766

Gnomad4 SAS exome

AF:

0.0000869

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000154

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense variant c.4718C>T(p.Ala1573Val) in AHDC1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.4718C>T variant has 0.005% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment.The amino acid Alanine at position 1573 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphe-Benign, SIFT-Damaging and Mutation Taster-polymorphism) predicts conflicting evidence on protein structure and function for this variant.The reference amino acid in AHDC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 24, 2023

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2173017). This variant has not been reported in the literature in individuals affected with AHDC1-related conditions. This variant is present in population databases (rs371087154, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1573 of the AHDC1 protein (p.Ala1573Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T;T;T

Eigen

Benign

-0.093

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.75

.;.;T;.;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.083

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N;N;N

MutationTaster

Benign

0.91

N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.7

N;.;N;.;.

REVEL

Benign

0.048

Sift

Uncertain

0.010

D;.;D;.;.

Sift4G

Uncertain

0.032

D;.;D;.;.

Polyphen

0.072

B;B;B;B;B

Vest4

0.30

MutPred

0.19

Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);

MVP

0.19

MPC

1.2

ClinPred

0.094

GERP RS

4.4

Varity_R

0.12

gMVP

0.46

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