9-132878222-G-T

Variant names:

• chr9-132878222-G-T
• rs370307434
• NM_152572.3:c.34C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152572.3(AK8):​c.34C>A​(p.Pro12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: AK8 NM_152572.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 2 publications found

Genes affected

AK8 (HGNC:26526): (adenylate kinase 8) Enables AMP binding activity and nucleobase-containing compound kinase activity. Involved in nucleoside diphosphate phosphorylation and nucleoside triphosphate biosynthetic process. Located in 9+2 motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

SPACA9 (HGNC:1367): (sperm acrosome associated 9) Predicted to enable calcium-dependent protein binding activity. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40169558).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152572.3. 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
	AK8	NM_152572.3	MANE Select	c.34C>A	p.Pro12Thr	missense	Exon 1 of 13	NP_689785.1	Q96MA6-1
	AK8	NM_001371772.1		c.34C>A	p.Pro12Thr	missense	Exon 1 of 11	NP_001358701.1
	AK8	NM_001317959.2		c.-876C>A		5_prime_UTR	Exon 1 of 15	NP_001304888.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK8	ENST00000298545.4	TSL:1 MANE Select	c.34C>A	p.Pro12Thr	missense	Exon 1 of 13	ENSP00000298545.3	Q96MA6-1
	SPACA9	ENST00000372136.7	TSL:1	c.-252G>T		5_prime_UTR	Exon 1 of 4	ENSP00000361209.3	Q96E40-1
	AK8	ENST00000885294.1		c.34C>A	p.Pro12Thr	missense	Exon 1 of 13	ENSP00000555353.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000716 AC: 1 AN: 139650 AF XY: 0.0000133

Gnomad AFR exome AF: 0.0000966

Gnomad AMR exome AF: 0.00

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: 0.00000153 AC: 2 AN: 1306286 Hom.: 0 Cov.: 29 AF XY: 0.00000157 AC XY: 1 AN XY: 637502

African (AFR) AF: 0.0000378 AC: 1 AN: 26428

American (AMR) AF: 0.00 AC: 0 AN: 24976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18016

East Asian (EAS) AF: 0.00 AC: 0 AN: 34418

South Asian (SAS) AF: 0.00 AC: 0 AN: 61780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5022

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1034112

Other (OTH) AF: 0.00 AC: 0 AN: 53340

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000867 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.20
MVP		0.69
MPC		0.28
ClinPred		0.94	D
GERP RS		0.99
PromoterAI		0.021	Neutral
Varity_R		0.30
gMVP		0.45
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs370307434; hg19: chr9-135753609; COSMIC: COSV100049705; COSMIC: COSV100049705;