19-4207311-G-C

Position:

• chr19-4207311-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001393985.1(ANKRD24):​c.536G>C​(p.Arg179Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R179L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKRD24 NM_001393985.1 missense, splice_region
• Scores: Splicing: ADA: 0.0005166
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

Genes affected

ANKRD24 (HGNC:29424): (ankyrin repeat domain 24)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27068135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD24	NM_001393985.1	c.536G>C	p.Arg179Pro	missense_variant, splice_region_variant	8/22	ENST00000318934.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD24	ENST00000318934.9	c.536G>C	p.Arg179Pro	missense_variant, splice_region_variant	8/22	5	NM_001393985.1	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461468 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727034

Gnomad4 AFR exome AF: 0.0000598

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2022

The c.536G>C (p.R179P) alteration is located in exon 8 (coding exon 7) of the ANKRD24 gene. This alteration results from a G to C substitution at nucleotide position 536, causing the arginine (R) at amino acid position 179 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.71	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.65	N;N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.045	D;D;D;D
Polyphen		0.032	B;B;.;D
Vest4		0.59
MutPred		0.40		Loss of catalytic residue at R179 (P = 0.038);Loss of catalytic residue at R179 (P = 0.038);.;.;
MVP		0.70
MPC		0.96
ClinPred		0.78	D
GERP RS		3.6
Varity_R		0.32
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.090
SpliceAI score (max)		0.030		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: chr19-4207308;