1-27552016-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001371928.1(AHDC1):c.100A>C(p.Thr34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T34N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 0 hom., cov: 0)

Exomes 𝑓: 0.093 ( 66 hom. )

Failed GnomAD Quality Control

Consequence

AHDC1
NM_001371928.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.01

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P, ClinGen

AHDC1 links:

ENSG00000300470 (HGNC:):

ENSG00000300470 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001614362).

BP6

Variant 1-27552016-T-G is Benign according to our data. Variant chr1-27552016-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402347.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHDC1	NM_001371928.1 link	c.100A>C	p.Thr34Pro	missense_variant	Exon 8 of 9	ENST00000673934.1	NP_001358857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHDC1	ENST00000673934.1 link	c.100A>C	p.Thr34Pro	missense_variant	Exon 8 of 9		NM_001371928.1	ENSP00000501218.1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

3189

AN:

20524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.150

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.172

Gnomad FIN

AF:

0.0918

Gnomad MID

AF:

0.125

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.145

GnomAD2 exomes

AF:

0.322

AC:

1447

AN:

4494

AF XY:

0.307

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.377

Gnomad ASJ exome

AF:

0.230

Gnomad EAS exome

AF:

0.437

Gnomad FIN exome

AF:

0.466

Gnomad NFE exome

AF:

0.232

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0934

AC:

4941

AN:

52914

Hom.:

Cov.:

AF XY:

0.107

AC XY:

2742

AN XY:

25682

show subpopulations

African (AFR)

AF:

0.131

AC:

159

AN:

1216

American (AMR)

AF:

0.275

AC:

296

AN:

1078

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

AN:

686

East Asian (EAS)

AF:

0.160

AC:

127

AN:

796

South Asian (SAS)

AF:

0.335

AC:

991

AN:

2960

European-Finnish (FIN)

AF:

0.331

AC:

727

AN:

2194

Middle Eastern (MID)

AF:

0.107

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.0561

AC:

2343

AN:

41756

Other (OTH)

AF:

0.0898

AC:

185

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

178

356

534

712

890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.155

AC:

3190

AN:

20550

Hom.:

Cov.:

AF XY:

0.154

AC XY:

1480

AN XY:

9624

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.143

AC:

782

AN:

5464

American (AMR)

AF:

0.118

AC:

230

AN:

1952

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

AN:

552

East Asian (EAS)

AF:

0.165

AC:

AN:

508

South Asian (SAS)

AF:

0.171

AC:

AN:

516

European-Finnish (FIN)

AF:

0.0918

AC:

103

AN:

1122

Middle Eastern (MID)

AF:

0.132

AC:

AN:

European-Non Finnish (NFE)

AF:

0.175

AC:

1761

AN:

10066

Other (OTH)

AF:

0.143

AC:

AN:

230

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.294

Heterozygous variant carriers

232

465

697

930

1162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.498

Hom.:

ExAC

AF:

0.00991

AC:

160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: only coveraged in 169 individuals in ExAC - looks like exome FP. LOF variants in this gene associated with syndromic expressive language delay, hypotonia & sleep apnoea, some overlap with dysmorphic features however all affected had hypoplasia of the corpus callosum, which was not seen in this individual -

not provided

Benign:1

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.033

T;T;T;T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.36

.;.;T;.;.

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N;N;N

PhyloP100

2.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.46

N;.;N;.;.

REVEL

Benign

0.23

Sift

Uncertain

0.0060

D;.;D;.;.

Sift4G

Benign

0.19

T;.;T;.;.

Polyphen

0.0

B;B;B;B;B

Vest4

0.38

MPC

1.5

ClinPred

0.030

GERP RS

0.51

Varity_R

0.20

gMVP

0.085

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over