9-127868455-G-T

Variant names:

• chr9-127868455-G-T
• rs104894101
• NM_000476.3:c.382C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_000476.3(AK1):​c.382C>A​(p.Arg128Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AK1 NM_000476.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.989
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000257524 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.289).
• BP7: Synonymous conserved (PhyloP=0.989 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	NM_000476.3	MANE Select	c.382C>A	p.Arg128Arg	synonymous	Exon 6 of 7	NP_000467.1
	AK1	NM_001318122.2		c.430C>A	p.Arg144Arg	synonymous	Exon 5 of 6	NP_001305051.1
	AK1	NM_001318121.1		c.382C>A	p.Arg128Arg	synonymous	Exon 6 of 7	NP_001305050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK1	ENST00000644144.2	MANE Select	c.382C>A	p.Arg128Arg	synonymous	Exon 6 of 7	ENSP00000494600.1
	ENSG00000257524	ENST00000646171.1		n.*415C>A		non_coding_transcript_exon	Exon 12 of 13	ENSP00000495484.1
	ENSG00000257524	ENST00000646171.1		n.*415C>A		3_prime_UTR	Exon 12 of 13	ENSP00000495484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456108 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 723734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 43934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 84952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109402

Other (OTH) AF: 0.00 AC: 0 AN: 60188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	4.6
DANN	Benign	0.86
PhyloP100		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs104894101; hg19: chr9-130630734;