chr19-17281955-G-A

Variant names:

• chr19-17281955-G-A
• rs903707304
• NM_152363.6:c.35G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152363.6(ANKLE1):​c.35G>A​(p.Arg12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,381,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKLE1 NM_152363.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094465554).

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.35G>A	p.Arg12Gln	missense	Exon 1 of 9	NP_689576.6
	ANKLE1	NM_001278444.2		c.35G>A	p.Arg12Gln	missense	Exon 1 of 8	NP_001265373.2
	ANKLE1	NM_001278445.2		c.-3G>A		5_prime_UTR	Exon 1 of 9	NP_001265374.2	Q8NAG6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKLE1	ENST00000404085.7	TSL:2 MANE Select	c.35G>A	p.Arg12Gln	missense	Exon 1 of 9	ENSP00000384008.3	Q8NAG6-2
	ANKLE1	ENST00000394458.7	TSL:1	c.197G>A	p.Arg66Gln	missense	Exon 1 of 9	ENSP00000377971.4	A0A499FJM0
	ENSG00000269307	ENST00000596542.1	TSL:2	n.*401-107G>A		intron	N/A	ENSP00000469159.2	M0QXG9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1381948 Hom.: 0 Cov.: 34 AF XY: 0.00000293 AC XY: 2 AN XY: 681614

African (AFR) AF: 0.00 AC: 0 AN: 31420

American (AMR) AF: 0.00 AC: 0 AN: 35532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25078

East Asian (EAS) AF: 0.00 AC: 0 AN: 35636

South Asian (SAS) AF: 0.00 AC: 0 AN: 79060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5040

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077372

Other (OTH) AF: 0.00 AC: 0 AN: 57684

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.15
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.29	T
Vest4		0.22
MVP		0.16
MPC		0.66
ClinPred		0.42	T
GERP RS		0.020
PromoterAI		-0.031	Neutral
gMVP		0.23
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs903707304; hg19: chr19-17392764;