rs116298211

chr14-96486941-T-Cchr14-96486941-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5 BP4_Moderate

The NM_152327.5(AK7):c.2018T>C(p.Leu673Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,614,046 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L673R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: AK7 NM_152327.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:1
• Conservation: PhyloP100: 6.01

Genes affected

AK7 (HGNC:20091): (adenylate kinase 7) This gene encodes a member of the adenylate kinase family of enzymes. The encoded enzyme is a phosphotransferase that catalyzes the reversible phosphorylation of adenine nucleotides. This enzyme plays a role in energy homeostasis of the cell. Alternative splicing results in multiple transcript variants. Mutations in the mouse gene are associated with primary ciliary dyskinesia. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-96486941-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 523614.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08193272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AK7	NM_152327.5	c.2018T>C	p.Leu673Pro	missense_variant	17/18	ENST00000267584.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK7	ENST00000267584.9	c.2018T>C	p.Leu673Pro	missense_variant	17/18	1	NM_152327.5	P1
AK7	ENST00000554706.1	c.284T>C	p.Leu95Pro	missense_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00146 AC: 368 AN: 251406 Hom.: 1 AF XY: 0.00152 AC XY: 206 AN XY: 135874

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00236 AC: 3451 AN: 1461742 Hom.: 7 Cov.: 31 AF XY: 0.00228 AC XY: 1657 AN XY: 727188

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00291

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152304 Hom.: 0 Cov.: 31 AF XY: 0.00128 AC XY: 95 AN XY: 74476

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00201 Hom.: 1

Bravo AF: 0.00138

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00167 AC: 203

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spermatogenic failure 27 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Oct 15, 2018

This variant is interpreted as Likely Pathogenic, for Spermatogenic failure 27, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/29365104). PM1-Supporting => PM1 downgraded in strength to Supporting (https://www.uniprot.org/uniprot/Q96M32). PM2-Supporting => PM2 downgraded in strength to Supporting. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.082	T
MetaSVM	Uncertain	0.037	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.83
MPC		0.96
ClinPred		0.090	T
GERP RS		5.5
Varity_R		0.92
gMVP		0.86

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: rs116298211; hg19: chr14-96953278;