9-132792656-G-A

Variant names:

• chr9-132792656-G-A
• rs140084214
• NM_152572.3:c.1099C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152572.3(AK8):​c.1099C>T​(p.Arg367Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,554,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R367H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: AK8 NM_152572.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.434
• Publications: 3 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069847107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK8	NM_152572.3	c.1099C>T	p.Arg367Cys	missense_variant	Exon 11 of 13	ENST00000298545.4	NP_689785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK8	ENST00000298545.4	c.1099C>T	p.Arg367Cys	missense_variant	Exon 11 of 13	1	NM_152572.3	ENSP00000298545.3
AK8	ENST00000476719.1	n.1536C>T		non_coding_transcript_exon_variant	Exon 10 of 12	5
AK8	ENST00000477396.5	n.2014C>T		non_coding_transcript_exon_variant	Exon 13 of 15	2

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000513 AC: 83 AN: 161868 AF XY: 0.000550

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.0000794

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000579

Gnomad NFE exome AF: 0.000940

Gnomad OTH exome AF: 0.000446

GnomAD4 exome AF: 0.000771 AC: 1081 AN: 1401778 Hom.: 0 Cov.: 30 AF XY: 0.000763 AC XY: 528 AN XY: 691888

African (AFR) AF: 0.000157 AC: 5 AN: 31844

American (AMR) AF: 0.0000828 AC: 3 AN: 36248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36196

South Asian (SAS) AF: 0.000214 AC: 17 AN: 79362

European-Finnish (FIN) AF: 0.000343 AC: 17 AN: 49500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.000942 AC: 1019 AN: 1081318

Other (OTH) AF: 0.000345 AC: 20 AN: 57992

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74518

African (AFR) AF: 0.000264 AC: 11 AN: 41594

American (AMR) AF: 0.000131 AC: 2 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000955 AC: 65 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000427

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000460 AC: 2

ESP6500EA AF: 0.000468 AC: 4

ExAC AF: 0.000273 AC: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1099C>T (p.R367C) alteration is located in exon 11 (coding exon 11) of the AK8 gene. This alteration results from a C to T substitution at nucleotide position 1099, causing the arginine (R) at amino acid position 367 to be replaced by a cysteine (C). 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	0.085
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.43
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.17
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.044	D
Polyphen		0.0060	B
Vest4		0.16
MVP		0.36
MPC		0.26
ClinPred		0.023	T
GERP RS		4.0
Varity_R		0.072
gMVP		0.37
Mutation Taster		=100/0	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: rs140084214; hg19: chr9-135668043;