rs1225767489

Variant names:

• chr19-17282073-C-G
• rs1225767489
• NM_152363.6:c.79C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-17282073-C-G
• chr19-17282073-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152363.6(ANKLE1):​c.79C>G​(p.Leu27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,387,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: ANKLE1 NM_152363.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.620
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152363.6. 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
	ANKLE1	NM_152363.6	MANE Select	c.79C>G	p.Leu27Val	missense	Exon 2 of 9	NP_689576.6
	ANKLE1	NM_001278444.2		c.79C>G	p.Leu27Val	missense	Exon 2 of 8	NP_001265373.2
	ANKLE1	NM_001278443.2		c.46C>G	p.Leu16Val	missense	Exon 2 of 9	NP_001265372.2	A0A494C092

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE1	ENST00000404085.7	TSL:2 MANE Select	c.79C>G	p.Leu27Val	missense	Exon 2 of 9	ENSP00000384008.3	Q8NAG6-2
	ANKLE1	ENST00000394458.7	TSL:1	c.241C>G	p.Leu81Val	missense	Exon 2 of 9	ENSP00000377971.4	A0A499FJM0
	ENSG00000269307	ENST00000596542.1	TSL:2	n.*412C>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000469159.2	M0QXG9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000577 AC: 8 AN: 1387444 Hom.: 0 Cov.: 33 AF XY: 0.00000730 AC XY: 5 AN XY: 684732

African (AFR) AF: 0.00 AC: 0 AN: 31560

American (AMR) AF: 0.00 AC: 0 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25158

East Asian (EAS) AF: 0.00 AC: 0 AN: 35716

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078634

Other (OTH) AF: 0.00 AC: 0 AN: 57868

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.092	T
PhyloP100		0.62
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Benign	0.10	T
Sift4G	Uncertain	0.022	D
Vest4		0.26
MVP		0.61
MPC		0.71
ClinPred		0.85	D
GERP RS		4.1
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.55
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1225767489; hg19: chr19-17392882;