rs1289686779

Variant names:

• chr5-75091401-C-A
• rs1289686779
• NM_001372053.1:c.5332G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-75091401-C-A
• chr5-75091401-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP3_Moderate

The NM_001372053.1(ANKRD31):​c.5332G>T​(p.Glu1778*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000731 in 1,368,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ANKRD31 NM_001372053.1 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.55
• Publications: 0 publications found

Genes affected

ANKRD31 (HGNC:26853): (ankyrin repeat domain 31) This gene encodes a protein containing multiple ankyrin repeats. Ankyrin domains function in protein-protein interactions in a variety of cellular processes. Mutations in this gene are associated with a Rett syndrome (RTT)-like phenotype. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372053.1. 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
	ANKRD31	NM_001372053.1	MANE Select	c.5332G>T	p.Glu1778*	stop_gained splice_region	Exon 23 of 26	NP_001358982.1	D6RJB7
	ANKRD31	NM_001164443.1		c.5161G>T	p.Glu1721*	stop_gained splice_region	Exon 22 of 25	NP_001157915.1	Q8N7Z5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD31	ENST00000506364.6	TSL:5 MANE Select	c.5332G>T	p.Glu1778*	stop_gained splice_region	Exon 23 of 26	ENSP00000427262.2	D6RJB7
	ANKRD31	ENST00000274361.3	TSL:5	c.5161G>T	p.Glu1721*	stop_gained splice_region	Exon 22 of 25	ENSP00000274361.3	Q8N7Z5
	ANKRD31	ENST00000504022.1	TSL:5	n.2122G>T		splice_region non_coding_transcript_exon	Exon 11 of 14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1368192 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 674562

African (AFR) AF: 0.00 AC: 0 AN: 30468

American (AMR) AF: 0.00 AC: 0 AN: 30364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24202

East Asian (EAS) AF: 0.00 AC: 0 AN: 35610

South Asian (SAS) AF: 0.00 AC: 0 AN: 76146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1073790

Other (OTH) AF: 0.00 AC: 0 AN: 57240

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	49
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.6
Vest4		0.16
GERP RS		4.4
Mutation Taster		=45/155	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1289686779; hg19: chr5-74387226;