9-127868360-A-G

Variant names:

• chr9-127868360-A-G
• rs913986
• NM_000476.3:c.477T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_000476.3(AK1):​c.477T>C​(p.Pro159Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,609,908 control chromosomes in the GnomAD database, including 804,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75914 hom., cov: 33)
  • Exomes 𝑓: 1.0 (728502 hom.)
• Consequence: AK1 NM_000476.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.39
• Publications: 16 publications found

Genes affected

AK1 (HGNC:361): (adenylate kinase 1) This gene encodes an adenylate kinase enzyme involved in energy metabolism and homeostasis of cellular adenine nucleotide ratios in different intracellular compartments. This gene is highly expressed in skeletal muscle, brain and erythrocytes. Certain mutations in this gene resulting in a functionally inadequate enzyme are associated with a rare genetic disorder causing nonspherocytic hemolytic anemia. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene shares readthrough transcripts with the upstream ST6GALNAC6 gene. [provided by RefSeq, Jan 2022]

AK1 Gene-Disease associations (from GenCC):

• hemolytic anemia due to adenylate kinase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000257524 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.202).
• BP6: Variant 9-127868360-A-G is Benign according to our data. Variant chr9-127868360-A-G is described in ClinVar as Benign. ClinVar VariationId is 439396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000476.3. 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
	AK1	NM_000476.3	MANE Select	c.477T>C	p.Pro159Pro	synonymous	Exon 6 of 7	NP_000467.1	P00568
	AK1	NM_001318122.2		c.525T>C	p.Pro175Pro	synonymous	Exon 5 of 6	NP_001305051.1	Q5T9B7
	AK1	NM_001318121.1		c.477T>C	p.Pro159Pro	synonymous	Exon 6 of 7	NP_001305050.1	Q6FGX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	ENST00000644144.2	MANE Select	c.477T>C	p.Pro159Pro	synonymous	Exon 6 of 7	ENSP00000494600.1	P00568
	ENSG00000257524	ENST00000646171.1		n.*510T>C		non_coding_transcript_exon	Exon 12 of 13	ENSP00000495484.1	A0A2R8YFX0
	ENSG00000257524	ENST00000646171.1		n.*510T>C		3_prime_UTR	Exon 12 of 13	ENSP00000495484.1	A0A2R8YFX0

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151957 AN: 152206 Hom.: 75855 Cov.: 33

Gnomad AFR AF: 0.994

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 243096 AN: 243212 AF XY: 1.00

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1457292 AN: 1457584 Hom.: 728502 Cov.: 68 AF XY: 1.00 AC XY: 724496 AN XY: 724632

African (AFR) AF: 0.992 AC: 33173 AN: 33432

American (AMR) AF: 1.00 AC: 44154 AN: 44164

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26022 AN: 26022

East Asian (EAS) AF: 1.00 AC: 39603 AN: 39604

South Asian (SAS) AF: 1.00 AC: 85326 AN: 85326

European-Finnish (FIN) AF: 1.00 AC: 52916 AN: 52916

Middle Eastern (MID) AF: 1.00 AC: 5550 AN: 5550

European-Non Finnish (NFE) AF: 1.00 AC: 1110358 AN: 1110362

Other (OTH) AF: 1.00 AC: 60190 AN: 60208

GnomAD4 genome AF: 0.998 AC: 152075 AN: 152324 Hom.: 75914 Cov.: 33 AF XY: 0.999 AC XY: 74371 AN XY: 74478

African (AFR) AF: 0.994 AC: 41335 AN: 41570

American (AMR) AF: 0.999 AC: 15301 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5174 AN: 5174

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68018 AN: 68022

Other (OTH) AF: 1.00 AC: 2111 AN: 2112

Alfa AF: 1.00 Hom.: 47449

Bravo AF: 0.998

Asia WGS AF: 0.999 AC: 3475 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hemolytic anemia due to adenylate kinase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.097
DANN	Benign	0.65
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs913986; hg19: chr9-130630639; COSMIC: COSV108078537; COSMIC: COSV108078537;