1-9244919-CCCCAGGCA-C

Position:

• chr1-9244919-CCCCAGGCA-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_004285.4(H6PD):​c.-7_1del variant causes a splice acceptor, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,609,272 control chromosomes in the GnomAD database, including 18,758 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1493 hom., cov: 30)
  • Exomes 𝑓: 0.15 (17265 hom.)
• Consequence: H6PD NM_004285.4 splice_acceptor, 5_prime_UTR, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.77

Genes affected

H6PD (HGNC:4795): (hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase) There are 2 forms of glucose-6-phosphate dehydrogenase. G form is X-linked and H form, encoded by this gene, is autosomally linked. This H form shows activity with other hexose-6-phosphates, especially galactose-6-phosphate, whereas the G form is specific for glucose-6-phosphate. Both forms are present in most tissues, but H form is not found in red cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.26767677 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 0 (no position change), new splice context is: tgtctctctttgcaccccAGgca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 1-9244919-CCCCAGGCA-C is Benign according to our data. Variant chr1-9244919-CCCCAGGCA-C is described in ClinVar as [Benign]. Clinvar id is 402919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-9244919-CCCCAGGCA-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H6PD	NM_004285.4	c.-7_1del		splice_acceptor_variant, 5_prime_UTR_variant, intron_variant	2/5	ENST00000377403.7	NP_004276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H6PD	ENST00000377403.7	c.-7_1del		splice_acceptor_variant, 5_prime_UTR_variant, intron_variant	2/5	1	NM_004285.4	ENSP00000366620	P1
H6PD	ENST00000602477.1	c.27_34del	p.Pro10ValfsTer38	splice_acceptor_variant, coding_sequence_variant, intron_variant	2/5	1		ENSP00000473348

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18716 AN: 152034 Hom.: 1484 Cov.: 30

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.112

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.159 AC: 39376 AN: 247588 Hom.: 3814 AF XY: 0.154 AC XY: 20680 AN XY: 133960

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.0853

Gnomad SAS exome AF: 0.154

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.146 AC: 213384 AN: 1457120 Hom.: 17265 AF XY: 0.147 AC XY: 106572 AN XY: 725118

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.316

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.123 AC: 18744 AN: 152152 Hom.: 1493 Cov.: 30 AF XY: 0.128 AC XY: 9535 AN XY: 74380

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.0826

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.126

Alfa AF: 0.140 Hom.: 289

Bravo AF: 0.123

Asia WGS AF: 0.121 AC: 424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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 in 1000Genomes: 255/2178= 11.71% -

Cortisone reductase deficiency 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-9304978;