rs143346525

chr1-27550606-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001371928.1(AHDC1):c.1510G>A(p.Val504Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,613,808 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V504V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: AHDC1 NM_001371928.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.748

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065502524).
• BP6: Variant 1-27550606-C-T is Benign according to our data. Variant chr1-27550606-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-27550606-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (266/152410) while in subpopulation NFE AF= 0.00303 (206/68048). AF 95% confidence interval is 0.00269. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 266 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHDC1	NM_001371928.1	c.1510G>A	p.Val504Met	missense_variant	8/9	ENST00000673934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHDC1	ENST00000673934.1	c.1510G>A	p.Val504Met	missense_variant	8/9		NM_001371928.1	P1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152292 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00171 AC: 428 AN: 250522 Hom.: 2 AF XY: 0.00178 AC XY: 241 AN XY: 135614

Gnomad AFR exome AF: 0.000619

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000602

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00309 AC: 4515 AN: 1461398 Hom.: 10 Cov.: 62 AF XY: 0.00301 AC XY: 2189 AN XY: 727036

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000340

Gnomad4 NFE exome AF: 0.00380

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152410 Hom.: 1 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74538

Gnomad4 AFR AF: 0.000937

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00264 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AHDC1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2019	- -

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

AHDC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.30	N
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N;N;N;N;N
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.23	N;.;N;.;.
REVEL	Benign	0.096
Sift	Uncertain	0.0070	D;.;D;.;.
Sift4G	Benign	0.19	T;.;T;.;.
Polyphen		0.97	D;D;D;D;D
Vest4		0.36
MVP		0.39
MPC		1.4
ClinPred		0.016	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs143346525; hg19: chr1-27877117; COSMIC: COSV55937961; COSMIC: COSV55937961;