rs199719452

Variant names:

• chr1-27551904-G-A
• rs199719452
• NM_001371928.1:c.212C>T

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.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:8
• Conservation: PhyloP100: 3.65
• Publications: 4 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=0.006389588).
• BP6: Variant 1-27551904-G-A is Benign according to our data. Variant chr1-27551904-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 623 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.212C>T	p.Thr71Ile	missense	Exon 8 of 9	NP_001358857.1	Q5TGY3
	AHDC1	NM_001029882.3		c.212C>T	p.Thr71Ile	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.212C>T	p.Thr71Ile	missense	Exon 8 of 9	ENSP00000501218.1	Q5TGY3
	AHDC1	ENST00000247087.10	TSL:5	c.212C>T	p.Thr71Ile	missense	Exon 5 of 6	ENSP00000247087.4	Q5TGY3
	AHDC1	ENST00000374011.6	TSL:5	c.212C>T	p.Thr71Ile	missense	Exon 6 of 7	ENSP00000363123.2	Q5TGY3

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

GnomAD2 exomes AF: 0.00383 AC: 873 AN: 228156 AF XY: 0.00375

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 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

African (AFR) AF: 0.000787 AC: 26 AN: 33024

American (AMR) AF: 0.00140 AC: 61 AN: 43660

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25264

East Asian (EAS) AF: 0.00 AC: 0 AN: 39366

South Asian (SAS) AF: 0.000956 AC: 81 AN: 84712

European-Finnish (FIN) AF: 0.00461 AC: 232 AN: 50358

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5680

European-Non Finnish (NFE) AF: 0.00735 AC: 8090 AN: 1100952

Other (OTH) AF: 0.00371 AC: 221 AN: 59512

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

African (AFR) AF: 0.00150 AC: 62 AN: 41268

American (AMR) AF: 0.00315 AC: 48 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00147 AC: 7 AN: 4746

European-Finnish (FIN) AF: 0.00407 AC: 43 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00673 AC: 456 AN: 67738

Other (OTH) AF: 0.00334 AC: 7 AN: 2094

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

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)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.049	D
Polyphen		0.0090	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
Mutation Taster		=100/0	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: rs199719452; hg19: chr1-27878415; COSMIC: COSV99059873; COSMIC: COSV99059873;