19-17282128-A-T

Variant names:

• chr19-17282128-A-T
• NM_152363.6:c.134A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152363.6(ANKLE1):​c.134A>T​(p.His45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,388,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKLE1 NM_152363.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.715

Genes affected

ANKLE1 (HGNC:26812): (ankyrin repeat and LEM domain containing 1) Enables endonuclease activity. Involved in positive regulation of response to DNA damage stimulus and protein export from nucleus. Located in cytosol and nucleoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269307 (HGNC:):

USHBP1 (HGNC:24058): (USH1 protein network component harmonin binding protein 1) Enables PDZ domain binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKLE1	NM_152363.6	c.134A>T	p.His45Leu	missense_variant	Exon 2 of 9	ENST00000404085.7	NP_689576.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKLE1	ENST00000404085.7	c.134A>T	p.His45Leu	missense_variant	Exon 2 of 9	2	NM_152363.6	ENSP00000384008.3
ENSG00000269307	ENST00000596542.1	n.*467A>T		non_coding_transcript_exon_variant	Exon 8 of 10	2		ENSP00000469159.2
ENSG00000269307	ENST00000596542.1	n.*467A>T		3_prime_UTR_variant	Exon 8 of 10	2		ENSP00000469159.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1388060 Hom.: 0 Cov.: 84 AF XY: 0.00000146 AC XY: 1 AN XY: 684692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.94
Eigen	Benign	0.036
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.19	T
PrimateAI	Pathogenic	0.88	D
REVEL	Uncertain	0.48
Sift4G	Pathogenic	0.0	D;D
Vest4		0.64
MVP		0.58
MPC		0.74
ClinPred		0.85	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-17392937;