rs4947012

Variant names:

• chr6-109691071-A-G
• rs4947012
• NM_001145128.3:c.-12+76T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001329603.2(AK9):​c.-612T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 320,516 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (176 hom., cov: 32)
  • Exomes 𝑓: 0.048 (269 hom.)
• Consequence: AK9 NM_001329603.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.543

Genes affected

AK9 (HGNC:33814): (adenylate kinase 9) The protein encoded by this gene catalyzes the interconversion of nucleosides, possessing both nucleoside monophosphate and diphosphate kinase activities. The encoded protein uses these interconversions to maintain nucleoside homeostasis. [provided by RefSeq, Jul 2016]

FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-109691071-A-G is Benign according to our data. Variant chr6-109691071-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 668144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK9	NM_001145128.3	c.-12+76T>C		intron_variant	Intron 1 of 40	ENST00000424296.7	NP_001138600.2
FIG4	NM_014845.6	c.-365A>G		upstream_gene_variant		ENST00000230124.8	NP_055660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK9	ENST00000424296.7	c.-12+76T>C		intron_variant	Intron 1 of 40	5	NM_001145128.3	ENSP00000410186.2
FIG4	ENST00000230124.8	c.-365A>G		upstream_gene_variant		1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.0424 AC: 6444 AN: 152118 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0890

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0506

Gnomad OTH AF: 0.0450

GnomAD4 exome AF: 0.0481 AC: 8088 AN: 168280 Hom.: 269 AF XY: 0.0495 AC XY: 4315 AN XY: 87196

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.0910

Gnomad4 ASJ exome AF: 0.0591

Gnomad4 EAS exome AF: 0.0167

Gnomad4 SAS exome AF: 0.0747

Gnomad4 FIN exome AF: 0.0297

Gnomad4 NFE exome AF: 0.0471

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0424 AC: 6459 AN: 152236 Hom.: 176 Cov.: 32 AF XY: 0.0421 AC XY: 3132 AN XY: 74432

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.0729

Gnomad4 ASJ AF: 0.0634

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.0889

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0506

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0441 Hom.: 29

Bravo AF: 0.0454

Asia WGS AF: 0.0590 AC: 204 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.8
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs4947012; hg19: chr6-110012274;