chr19-17283242-C-T

Variant names:

• chr19-17283242-C-T
• rs59119993
• NM_152363.6:c.478C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152363.6(ANKLE1):​c.478C>T​(p.Pro160Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,611,650 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: ANKLE1 NM_152363.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.17
• Publications: 6 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026779175).
• BP6: Variant 19-17283242-C-T is Benign according to our data. Variant chr19-17283242-C-T is described in ClinVar as Benign. ClinVar VariationId is 784390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00935 (1424/152276) while in subpopulation AFR AF = 0.0319 (1326/41546). AF 95% confidence interval is 0.0305. There are 18 homozygotes in GnomAd4. There are 685 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

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.478C>T	p.Pro160Ser	missense	Exon 5 of 9	NP_689576.6
	ANKLE1	NM_001278444.2		c.478C>T	p.Pro160Ser	missense	Exon 5 of 8	NP_001265373.2
	ANKLE1	NM_001278443.2		c.445C>T	p.Pro149Ser	missense	Exon 5 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.478C>T	p.Pro160Ser	missense	Exon 5 of 9	ENSP00000384008.3	Q8NAG6-2
	ANKLE1	ENST00000394458.7	TSL:1	c.640C>T	p.Pro214Ser	missense	Exon 5 of 9	ENSP00000377971.4	A0A499FJM0
	ANKLE1	ENST00000598347.2	TSL:2	c.478C>T	p.Pro160Ser	missense	Exon 5 of 8	ENSP00000470895.2	M0R002

Frequencies

GnomAD3 genomes AF: 0.00934 AC: 1421 AN: 152158 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00251 AC: 625 AN: 249122 AF XY: 0.00176

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00333

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00115 AC: 1673 AN: 1459374 Hom.: 26 Cov.: 36 AF XY: 0.00102 AC XY: 740 AN XY: 725762

African (AFR) AF: 0.0371 AC: 1241 AN: 33418

American (AMR) AF: 0.00146 AC: 65 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00361 AC: 94 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52914

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0000873 AC: 97 AN: 1110554

Other (OTH) AF: 0.00262 AC: 158 AN: 60270

GnomAD4 genome AF: 0.00935 AC: 1424 AN: 152276 Hom.: 18 Cov.: 32 AF XY: 0.00920 AC XY: 685 AN XY: 74454

African (AFR) AF: 0.0319 AC: 1326 AN: 41546

American (AMR) AF: 0.00399 AC: 61 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00353 Hom.: 22

Bravo AF: 0.0108

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.25
DANN	Benign	0.55
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.2
PrimateAI	Benign	0.24	T
REVEL	Benign	0.097
Sift4G	Benign	0.73	T
Vest4		0.077
MVP		0.17
MPC		0.17
ClinPred		0.00083	T
GERP RS		-0.53
PromoterAI		-0.055	Neutral
gMVP		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs59119993; hg19: chr19-17394051;