rs200591586

Variant names:

• chr6-32518080-G-A
• rs200591586
• NM_002125.4:c.764-3C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_002125.4(HLA-DRB5):​c.764-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.00023 (0 hom., cov: 1)
  • Exomes 𝑓: 0.000022 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB5 NM_002125.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001011
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.410
• Publications: 4 publications found

Genes affected

HLA-DRB5 (HGNC:4953): (major histocompatibility complex, class II, DR beta 5) HLA-DRB5 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene. [provided by RefSeq, Feb 2020]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-32518080-G-A is Benign according to our data. Variant chr6-32518080-G-A is described in ClinVar as [Benign]. Clinvar id is 252599.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.764-3C>T		splice_region_variant, intron_variant	Intron 4 of 5	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.764-3C>T		splice_region_variant, intron_variant	Intron 4 of 5		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4	c.764-3C>T		splice_region_variant, intron_variant	Intron 4 of 5	6	NM_002125.4	ENSP00000364114.3
HLA-DRB5	ENST00000714490.1	c.674-3C>T		splice_region_variant, intron_variant	Intron 4 of 5			ENSP00000519744.1

Frequencies

GnomAD3 genomes AF: 0.000234 AC: 9 AN: 38508 Hom.: 0 Cov.: 1

Gnomad AFR AF: 0.000190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000346

Gnomad ASJ AF: 0.00191

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000418

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00235

GnomAD2 exomes AF: 0.00112 AC: 80 AN: 71116 AF XY: 0.00130

Gnomad AFR exome AF: 0.000223

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.00120

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000220 AC: 9 AN: 409344 Hom.: 1 Cov.: 0 AF XY: 0.0000289 AC XY: 6 AN XY: 207632

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

African (AFR) AF: 0.00 AC: 0 AN: 9630

American (AMR) AF: 0.00 AC: 0 AN: 8886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4242

East Asian (EAS) AF: 0.00 AC: 0 AN: 12400

South Asian (SAS) AF: 0.00 AC: 0 AN: 32062

European-Finnish (FIN) AF: 0.000524 AC: 8 AN: 15274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1362

European-Non Finnish (NFE) AF: 0.00000325 AC: 1 AN: 307656

Other (OTH) AF: 0.00 AC: 0 AN: 17832

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000234 AC: 9 AN: 38524 Hom.: 0 Cov.: 1 AF XY: 0.000213 AC XY: 4 AN XY: 18796

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

African (AFR) AF: 0.000190 AC: 2 AN: 10552

American (AMR) AF: 0.000345 AC: 1 AN: 2898

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 1 AN: 524

East Asian (EAS) AF: 0.00 AC: 0 AN: 1418

South Asian (SAS) AF: 0.00 AC: 0 AN: 1680

European-Finnish (FIN) AF: 0.000418 AC: 1 AN: 2394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.000163 AC: 3 AN: 18406

Other (OTH) AF: 0.00226 AC: 1 AN: 442

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0581 Hom.: 8

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.49
PhyloP100		0.41
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.010		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: rs200591586; hg19: chr6-32485857;