Genetic Variant AHDC1:p.Thr1597Ala (chr1-27547327-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001371928.1(AHDC1):c.4789A>G(p.Thr1597Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,547,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1597R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

AHDC1
NM_001371928.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.56

Publications

0 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: Illumina, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22169536).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371928.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHDC1	NM_001371928.1	MANE Select	c.4789A>G	p.Thr1597Ala	missense	Exon 8 of 9	NP_001358857.1	Q5TGY3
	AHDC1	NM_001029882.3		c.4789A>G	p.Thr1597Ala	missense	Exon 6 of 7	NP_001025053.1	Q5TGY3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AHDC1	ENST00000673934.1	MANE Select	c.4789A>G	p.Thr1597Ala	missense	Exon 8 of 9	ENSP00000501218.1	Q5TGY3
AHDC1	ENST00000247087.10	TSL:5	c.4789A>G	p.Thr1597Ala	missense	Exon 5 of 6	ENSP00000247087.4	Q5TGY3
AHDC1	ENST00000374011.6	TSL:5	c.4789A>G	p.Thr1597Ala	missense	Exon 6 of 7	ENSP00000363123.2	Q5TGY3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000205

AC:

AN:

194754

AF XY:

0.0000192

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000717

AC:

AN:

1395156

Hom.:

Cov.:

AF XY:

0.00000871

AC XY:

AN XY:

688546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31002

American (AMR)

AF:

0.00

AC:

AN:

32922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21528

East Asian (EAS)

AF:

0.00

AC:

AN:

39232

South Asian (SAS)

AF:

0.000132

AC:

AN:

75574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081920

Other (OTH)

AF:

0.00

AC:

AN:

57388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.69

M_CAP

Benign

0.016

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.34

PhyloP100

3.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.5

REVEL

Benign

0.18

Sift

Uncertain

0.0050

Sift4G

Benign

0.091

Polyphen

0.98

Vest4

0.29

MutPred

0.14

Loss of phosphorylation at T1597 (P = 0.006)

MVP

0.27

MPC

0.92

ClinPred

0.39

GERP RS

5.3

Varity_R

0.15

gMVP

0.28

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over