1-27552016-T-G

Variant names:

• chr1-27552016-T-G
• rs758473342
• NM_001371928.1:c.100A>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001371928.1(AHDC1):​c.100A>C​(p.Thr34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T34N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (0 hom., cov: 0)
  • Exomes 𝑓: 0.093 (66 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHDC1 NM_001371928.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.01

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001614362).
• BP6: Variant 1-27552016-T-G is Benign according to our data. Variant chr1-27552016-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402347.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHDC1	NM_001371928.1	c.100A>C	p.Thr34Pro	missense_variant	Exon 8 of 9	ENST00000673934.1	NP_001358857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHDC1	ENST00000673934.1	c.100A>C	p.Thr34Pro	missense_variant	Exon 8 of 9		NM_001371928.1	ENSP00000501218.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3189 AN: 20524 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.322 AC: 1447 AN: 4494 Hom.: 6 AF XY: 0.307 AC XY: 733 AN XY: 2388

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.437

Gnomad SAS exome AF: 0.321

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.321

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0934 AC: 4941 AN: 52914 Hom.: 66 Cov.: 0 AF XY: 0.107 AC XY: 2742 AN XY: 25682

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.0561

Gnomad4 OTH exome AF: 0.0898

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.155 AC: 3190 AN: 20550 Hom.: 0 Cov.: 0 AF XY: 0.154 AC XY: 1480 AN XY: 9624

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.0918

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.143

Alfa AF: 0.498 Hom.: 0

ExAC AF: 0.00991 AC: 160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: only coveraged in 169 individuals in ExAC - looks like exome FP. LOF variants in this gene associated with syndromic expressive language delay, hypotonia & sleep apnoea, some overlap with dysmorphic features however all affected had hypoplasia of the corpus callosum, which was not seen in this individual -

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.033	T;T;T;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.36	.;.;T;.;.
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.46	N;.;N;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;.;D;.;.
Sift4G	Benign	0.19	T;.;T;.;.
Polyphen		0.0	B;B;B;B;B
Vest4		0.38
MPC		1.5
ClinPred		0.030	T
GERP RS		0.51
Varity_R		0.20
gMVP		0.085

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: rs758473342; hg19: chr1-27878527; COSMIC: COSV55937873; COSMIC: COSV55937873;