1-77558599-T-C

Variant names:

• chr1-77558599-T-C
• rs6675743
• NM_174858.3:c.1621-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174858.3(AK5):​c.1621-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,554,816 control chromosomes in the GnomAD database, including 464,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39670 hom., cov: 31)
  • Exomes 𝑓: 0.78 (424409 hom.)
• Consequence: AK5 NM_174858.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003215
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02
• Publications: 12 publications found

Genes affected

AK5 (HGNC:365): (adenylate kinase 5) This gene encodes a member of the adenylate kinase family, which is involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. This member is related to the UMP/CMP kinase of several species. It is located in the cytosol and expressed exclusively in brain. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-77558599-T-C is Benign according to our data. Variant chr1-77558599-T-C is described in ClinVar as Benign. ClinVar VariationId is 402358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK5	NM_174858.3	c.1621-3T>C		splice_region_variant, intron_variant	Intron 13 of 13	ENST00000354567.7	NP_777283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK5	ENST00000354567.7	c.1621-3T>C		splice_region_variant, intron_variant	Intron 13 of 13	1	NM_174858.3	ENSP00000346577.2

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108815 AN: 151884 Hom.: 39655 Cov.: 31

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.691

GnomAD2 exomes AF: 0.751 AC: 185961 AN: 247626 AF XY: 0.748

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.847

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.745

Gnomad FIN exome AF: 0.725

Gnomad NFE exome AF: 0.786

Gnomad OTH exome AF: 0.721

GnomAD4 exome AF: 0.775 AC: 1087289 AN: 1402814 Hom.: 424409 Cov.: 23 AF XY: 0.772 AC XY: 541184 AN XY: 701146

African (AFR) AF: 0.581 AC: 18899 AN: 32510

American (AMR) AF: 0.840 AC: 37097 AN: 44160

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 15371 AN: 25762

East Asian (EAS) AF: 0.722 AC: 28453 AN: 39392

South Asian (SAS) AF: 0.683 AC: 57441 AN: 84048

European-Finnish (FIN) AF: 0.726 AC: 38713 AN: 53330

Middle Eastern (MID) AF: 0.635 AC: 3382 AN: 5328

European-Non Finnish (NFE) AF: 0.797 AC: 844473 AN: 1059854

Other (OTH) AF: 0.744 AC: 43460 AN: 58430

GnomAD4 genome AF: 0.716 AC: 108876 AN: 152002 Hom.: 39670 Cov.: 31 AF XY: 0.712 AC XY: 52883 AN XY: 74270

African (AFR) AF: 0.585 AC: 24230 AN: 41402

American (AMR) AF: 0.785 AC: 12007 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2098 AN: 3462

East Asian (EAS) AF: 0.738 AC: 3817 AN: 5172

South Asian (SAS) AF: 0.677 AC: 3261 AN: 4814

European-Finnish (FIN) AF: 0.715 AC: 7539 AN: 10540

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53652 AN: 68000

Other (OTH) AF: 0.689 AC: 1456 AN: 2114

Alfa AF: 0.755 Hom.: 41954

Bravo AF: 0.716

Asia WGS AF: 0.636 AC: 2213 AN: 3478

EpiCase AF: 0.768

EpiControl AF: 0.764

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.053
DANN	Benign	0.73
PhyloP100		-2.0
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0040
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: rs6675743; hg19: chr1-78024284; COSMIC: COSV60971818; COSMIC: COSV60971818;