14-96392259-G-C

Variant names:

• chr14-96392259-G-C
• rs760985683
• NM_152327.5:c.105G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152327.5(AK7):​c.105G>C​(p.Lys35Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K35K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AK7 NM_152327.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33
• Publications: 0 publications found

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]

AK7 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen
• spermatogenic failure 27

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152327.5. 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
	AK7	NM_152327.5	MANE Select	c.105G>C	p.Lys35Asn	missense splice_region	Exon 1 of 18	NP_689540.2	Q96M32
	AK7	NM_001350888.2		c.105G>C	p.Lys35Asn	missense splice_region	Exon 1 of 17	NP_001337817.1
	AK7	NM_001350890.2		c.105G>C	p.Lys35Asn	missense splice_region	Exon 1 of 17	NP_001337819.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK7	ENST00000267584.9	TSL:1 MANE Select	c.105G>C	p.Lys35Asn	missense splice_region	Exon 1 of 18	ENSP00000267584.4	Q96M32
	AK7	ENST00000856706.1		c.105G>C	p.Lys35Asn	missense splice_region	Exon 1 of 19	ENSP00000526765.1
	AK7	ENST00000856705.1		c.105G>C	p.Lys35Asn	missense splice_region	Exon 1 of 17	ENSP00000526764.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250162 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458654 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725772

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.0000224 AC: 1 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109364

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Benign	0.041	D
Sift4G	Benign	0.075	T
Polyphen		0.56	P
Vest4		0.56
MutPred		0.36		Loss of methylation at K35 (P = 0.0015)
MVP		0.71
MPC		0.24
ClinPred		0.93	D
GERP RS		4.7
PromoterAI		-0.32	Neutral
Varity_R		0.53
gMVP		0.67
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760985683; hg19: chr14-96858596;