1-27550881-C-T

Position:

• chr1-27550881-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.1235G>A​(p.Arg412His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,581,454 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R412C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (25 hom.)
• Consequence: AHDC1 NM_001371928.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.374

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048695207).
• BP6: Variant 1-27550881-C-T is Benign according to our data. Variant chr1-27550881-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-27550881-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00505 (769/152308) while in subpopulation AMR AF= 0.0104 (159/15312). AF 95% confidence interval is 0.00907. There are 1 homozygotes in gnomad4. There are 362 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 769 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHDC1	NM_001371928.1	c.1235G>A	p.Arg412His	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	c.1235G>A	p.Arg412His	missense_variant	8/9		NM_001371928.1	ENSP00000501218.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 769 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00694

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00553 AC: 1052 AN: 190110 Hom.: 8 AF XY: 0.00560 AC XY: 593 AN XY: 105926

Gnomad AFR exome AF: 0.000946

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.00929

Gnomad EAS exome AF: 0.0000654

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00709

Gnomad OTH exome AF: 0.00803

GnomAD4 exome AF: 0.00598 AC: 8547 AN: 1429146 Hom.: 25 Cov.: 57 AF XY: 0.00605 AC XY: 4297 AN XY: 709704

Gnomad4 AFR exome AF: 0.000760

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.00766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.00391

Gnomad4 NFE exome AF: 0.00656

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.00505 AC: 769 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00486 AC XY: 362 AN XY: 74462

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00694

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00643 Hom.: 0

Bravo AF: 0.00499

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.00543 AC: 44

ExAC AF: 0.00473 AC: 558

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	AHDC1: BS1, BS2 -

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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;T;T;T
Eigen	Benign	0.087
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.70	.;.;T;.;.
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.070	N;.;N;.;.
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;.;D;.;.
Sift4G	Benign	0.16	T;.;T;.;.
Polyphen		0.95	P;P;P;P;P
Vest4		0.36
MVP		0.11
MPC		1.4
ClinPred		0.018	T
GERP RS		3.9
Varity_R		0.21
gMVP		0.19

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: rs181285619; hg19: chr1-27877392;