NM_001371928.1:c.1235G>A

Variant names:

• chr1-27550881-C-T
• rs181285619
• NM_001371928.1:c.1235G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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
• Publications: 5 publications found

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)

ENSG00000300470 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 235372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 769 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.1235G>A	p.Arg412His	missense	Exon 8 of 9	NP_001358857.1	Q5TGY3
	AHDC1	NM_001029882.3		c.1235G>A	p.Arg412His	missense	Exon 6 of 7	NP_001025053.1	Q5TGY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHDC1	ENST00000673934.1	MANE Select	c.1235G>A	p.Arg412His	missense	Exon 8 of 9	ENSP00000501218.1	Q5TGY3
	AHDC1	ENST00000247087.10	TSL:5	c.1235G>A	p.Arg412His	missense	Exon 5 of 6	ENSP00000247087.4	Q5TGY3
	AHDC1	ENST00000374011.6	TSL:5	c.1235G>A	p.Arg412His	missense	Exon 6 of 7	ENSP00000363123.2	Q5TGY3

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

GnomAD2 exomes AF: 0.00553 AC: 1052 AN: 190110 AF XY: 0.00560

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 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

African (AFR) AF: 0.000760 AC: 25 AN: 32914

American (AMR) AF: 0.00658 AC: 275 AN: 41792

Ashkenazi Jewish (ASJ) AF: 0.00766 AC: 192 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 38514

South Asian (SAS) AF: 0.00384 AC: 318 AN: 82806

European-Finnish (FIN) AF: 0.00391 AC: 165 AN: 42164

Middle Eastern (MID) AF: 0.00823 AC: 47 AN: 5714

European-Non Finnish (NFE) AF: 0.00656 AC: 7228 AN: 1100990

Other (OTH) AF: 0.00502 AC: 297 AN: 59196

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

African (AFR) AF: 0.00115 AC: 48 AN: 41566

American (AMR) AF: 0.0104 AC: 159 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00694 AC: 472 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00569 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.37
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		0.95	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs181285619; hg19: chr1-27877392;