NM_002637.4:c.429C>T

Variant names:

• chrX-72695733-G-A
• rs138066694
• NM_002637.4:c.429C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002637.4(PHKA1):​c.429C>T​(p.Leu143Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,207,676 control chromosomes in the GnomAD database, including 643 homozygotes. There are 13,439 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (52 hom., 812 hem., cov: 22)
  • Exomes 𝑓: 0.036 (591 hom. 12627 hem.)
• Consequence: PHKA1 NM_002637.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.717
• Publications: 1 publications found

Genes affected

PHKA1 (HGNC:8925): (phosphorylase kinase regulatory subunit alpha 1) Phosphorylase kinase is a polymer of 16 subunits, four each of alpha, beta, gamma and delta. The alpha subunit includes the skeletal muscle and hepatic isoforms, and the skeletal muscle isoform is encoded by this gene. The beta subunit is the same in both the muscle and hepatic isoforms, and encoded by one gene. The gamma subunit also includes the skeletal muscle and hepatic isoforms, which are encoded by two different genes. The delta subunit is a calmodulin and can be encoded by three different genes. The gamma subunits contain the active site of the enzyme, whereas the alpha and beta subunits have regulatory functions controlled by phosphorylation. The delta subunit mediates the dependence of the enzyme on calcium concentration. Mutations in this gene cause glycogen storage disease type 9D, also known as X-linked muscle glycogenosis. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene. A pseudogene has been found on chromosome 1.[provided by RefSeq, Feb 2010]

PHKA1-AS1 (HGNC:40446): (PHKA1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-72695733-G-A is Benign according to our data. Variant chrX-72695733-G-A is described in ClinVar as Benign. ClinVar VariationId is 258785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.717 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0271 (3019/111244) while in subpopulation NFE AF = 0.0423 (2242/53031). AF 95% confidence interval is 0.0408. There are 52 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHKA1	NM_002637.4	c.429C>T	p.Leu143Leu	synonymous_variant	Exon 4 of 32	ENST00000373542.9	NP_002628.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHKA1	ENST00000373542.9	c.429C>T	p.Leu143Leu	synonymous_variant	Exon 4 of 32	1	NM_002637.4	ENSP00000362643.4

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 3020 AN: 111194 Hom.: 52 Cov.: 22

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00145

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00926

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.0295

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0366

GnomAD2 exomes AF: 0.0254 AC: 4649 AN: 183269 AF XY: 0.0249

Gnomad AFR exome AF: 0.00410

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0300

GnomAD4 exome AF: 0.0361 AC: 39596 AN: 1096432 Hom.: 591 Cov.: 30 AF XY: 0.0348 AC XY: 12627 AN XY: 362618

African (AFR) AF: 0.00455 AC: 120 AN: 26352

American (AMR) AF: 0.0183 AC: 644 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 832 AN: 19381

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30197

South Asian (SAS) AF: 0.00864 AC: 467 AN: 54067

European-Finnish (FIN) AF: 0.0189 AC: 768 AN: 40528

Middle Eastern (MID) AF: 0.0255 AC: 79 AN: 3095

European-Non Finnish (NFE) AF: 0.0418 AC: 35208 AN: 841634

Other (OTH) AF: 0.0321 AC: 1476 AN: 45979

GnomAD4 genome AF: 0.0271 AC: 3019 AN: 111244 Hom.: 52 Cov.: 22 AF XY: 0.0243 AC XY: 812 AN XY: 33436

African (AFR) AF: 0.00532 AC: 163 AN: 30639

American (AMR) AF: 0.0283 AC: 295 AN: 10434

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 122 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00929 AC: 24 AN: 2583

European-Finnish (FIN) AF: 0.0187 AC: 111 AN: 5942

Middle Eastern (MID) AF: 0.0279 AC: 6 AN: 215

European-Non Finnish (NFE) AF: 0.0423 AC: 2242 AN: 53031

Other (OTH) AF: 0.0362 AC: 55 AN: 1521

Alfa AF: 0.0330 Hom.: 239

Bravo AF: 0.0269

EpiCase AF: 0.0448

EpiControl AF: 0.0428

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jan 30, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease IXd Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 17, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.3
DANN	Benign	0.70
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs138066694; hg19: chrX-71915583;