5-75104473-C-T

Position:

• chr5-75104473-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001372053.1(ANKRD31):​c.5086G>A​(p.Gly1696Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000065 in 1,384,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: ANKRD31 NM_001372053.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

Genes affected

ANKRD31 (HGNC:26853): (ankyrin repeat domain 31) This gene encodes a protein containing multiple ankyrin repeats. Ankyrin domains function in protein-protein interactions in a variety of cellular processes. Mutations in this gene are associated with a Rett syndrome (RTT)-like phenotype. [provided by RefSeq, Apr 2017]

ANKRD31 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06157735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD31	NM_001372053.1	c.5086G>A	p.Gly1696Arg	missense_variant	22/26	ENST00000506364.6	NP_001358982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD31	ENST00000506364.6	c.5086G>A	p.Gly1696Arg	missense_variant	22/26	5	NM_001372053.1	ENSP00000427262.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000650 AC: 9 AN: 1384916 Hom.: 0 Cov.: 31 AF XY: 0.00000878 AC XY: 6 AN XY: 683378

Gnomad4 AFR exome AF: 0.000127

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: 0.0000691

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

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

Sep 16, 2021

The c.4915G>A (p.G1639R) alteration is located in exon 21 (coding exon 21) of the ANKRD31 gene. This alteration results from a G to A substitution at nucleotide position 4915, causing the glycine (G) at amino acid position 1639 to be replaced by an arginine (R). 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	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0029	.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	.;L
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.97	.;N
REVEL	Benign	0.042
Sift	Benign	0.45	.;T
Sift4G	Benign	0.15	T;T
Vest4		0.088
MutPred		0.41		.;Gain of catalytic residue at G1639 (P = 0.0107);
MVP		0.28
ClinPred		0.055	T
GERP RS		-3.7
Varity_R		0.040
gMVP		0.055

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

LitVar

Other links and lift over

dbSNP: rs1747166310; hg19: chr5-74400298;