rs7350

Variant names:

• chr11-119094338-G-A
• rs7350
• NM_002105.3:c.*625C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002105.3(H2AX):​c.*625C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,256 control chromosomes in the GnomAD database, including 7,913 homozygotes. 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: 𝑓 0.31 (7910 hom., cov: 33)
  • Exomes 𝑓: 0.26 (3 hom.)
• Consequence: H2AX NM_002105.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 14 publications found

Genes affected

H2AX (HGNC:4739): (H2A.X variant histone) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene encodes a replication-independent histone that is a member of the histone H2A family, and generates two transcripts through the use of the conserved stem-loop termination motif, and the polyA addition motif. [provided by RefSeq, Oct 2015]

DPAGT1 (HGNC:2995): (dolichyl-phosphate N-acetylglucosaminephosphotransferase 1) The protein encoded by this gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. This enzyme belongs to the glycosyltransferase family 4. This protein is an integral membrane protein of the endoplasmic reticulum. The congenital disorder of glycosylation type Ij is caused by mutation in the gene encoding this enzyme. [provided by RefSeq, Jul 2008]

DPAGT1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• DPAGT1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2AX	NM_002105.3	c.*625C>T		3_prime_UTR_variant	Exon 1 of 1	ENST00000530167.2	NP_002096.1
DPAGT1	XM_047426508.1	c.*2539-77C>T		intron_variant	Intron 9 of 9		XP_047282464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2AX	ENST00000530167.2	c.*625C>T		3_prime_UTR_variant	Exon 1 of 1	6	NM_002105.3	ENSP00000434024.1
H2AX	ENST00000375167.1	n.*504-77C>T		intron_variant	Intron 1 of 1	2		ENSP00000364310.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46810 AN: 152068 Hom.: 7904 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.257 AC: 18 AN: 70 Hom.: 3 Cov.: 0 AF XY: 0.190 AC XY: 11 AN XY: 58

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.258 AC: 16 AN: 62

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.308 AC: 46835 AN: 152186 Hom.: 7910 Cov.: 33 AF XY: 0.309 AC XY: 23020 AN XY: 74420

African (AFR) AF: 0.172 AC: 7157 AN: 41544

American (AMR) AF: 0.277 AC: 4233 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1557 AN: 3466

East Asian (EAS) AF: 0.493 AC: 2548 AN: 5170

South Asian (SAS) AF: 0.222 AC: 1072 AN: 4830

European-Finnish (FIN) AF: 0.408 AC: 4323 AN: 10600

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24790 AN: 67952

Other (OTH) AF: 0.338 AC: 716 AN: 2116

Alfa AF: 0.334 Hom.: 5188

Bravo AF: 0.296

Asia WGS AF: 0.311 AC: 1085 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.51
DANN	Benign	0.65
PhyloP100		-2.0
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: rs7350; hg19: chr11-118965048; COSMIC: COSV53829984; COSMIC: COSV53829984;