rs199719452

Positions:

• chr1-27551904-G-A

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.212C>T​(p.Thr71Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00586 in 1,593,968 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (31 hom.)
• Consequence: AHDC1 NM_001371928.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.65

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=0.006389588).
• BP6: Variant 1-27551904-G-A is Benign according to our data. Variant chr1-27551904-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00411 (623/151440) while in subpopulation NFE AF= 0.00673 (456/67738). AF 95% confidence interval is 0.00622. There are 3 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 623 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHDC1	NM_001371928.1	c.212C>T	p.Thr71Ile	missense_variant	8/9	ENST00000673934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHDC1	ENST00000673934.1	c.212C>T	p.Thr71Ile	missense_variant	8/9		NM_001371928.1	P1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 621 AN: 151326 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00407

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00673

Gnomad OTH AF: 0.00338

GnomAD3 exomes AF: 0.00383 AC: 873 AN: 228156 Hom.: 3 AF XY: 0.00375 AC XY: 469 AN XY: 125142

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00474

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00519

GnomAD4 exome AF: 0.00605 AC: 8721 AN: 1442528 Hom.: 31 Cov.: 49 AF XY: 0.00587 AC XY: 4195 AN XY: 715244

Gnomad4 AFR exome AF: 0.000787

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.000158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000956

Gnomad4 FIN exome AF: 0.00461

Gnomad4 NFE exome AF: 0.00735

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00411 AC: 623 AN: 151440 Hom.: 3 Cov.: 31 AF XY: 0.00384 AC XY: 284 AN XY: 73990

Gnomad4 AFR AF: 0.00150

Gnomad4 AMR AF: 0.00315

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00147

Gnomad4 FIN AF: 0.00407

Gnomad4 NFE AF: 0.00673

Gnomad4 OTH AF: 0.00334

Alfa AF: 0.00449 Hom.: 1

Bravo AF: 0.00398

ESP6500AA AF: 0.000956 AC: 4

ESP6500EA AF: 0.00509 AC: 42

ExAC AF: 0.00382 AC: 457

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	AHDC1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 30, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;T;T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0064	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N;.;N;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.011	D;.;D;.;.
Sift4G	Uncertain	0.049	D;.;D;.;.
Polyphen		0.0090	B;B;B;B;B
Vest4		0.15
MVP		0.082
MPC		1.3
ClinPred		0.015	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.16

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: rs199719452; hg19: chr1-27878415; COSMIC: COSV99059873; COSMIC: COSV99059873;