6-32530183-C-T

Variant names:

• chr6-32530183-C-T
• rs75457801
• NM_002125.4:c.42G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_002125.4(HLA-DRB5):​c.42G>A​(p.Lys14Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000855 in 1,169,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: HLA-DRB5 NM_002125.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.17
• Publications: 9 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-32530183-C-T is Benign according to our data. Variant chr6-32530183-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3770412.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.42G>A	p.Lys14Lys	synonymous_variant	Exon 1 of 6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.42G>A	p.Lys14Lys	synonymous_variant	Exon 1 of 6		XP_011512864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DRB5	ENST00000374975.4	c.42G>A	p.Lys14Lys	synonymous_variant	Exon 1 of 6	6	NM_002125.4	ENSP00000364114.3
HLA-DRB5	ENST00000714490.1	c.42G>A	p.Lys14Lys	synonymous_variant	Exon 1 of 6			ENSP00000519744.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 8.55e-7 AC: 1 AN: 1169380 Hom.: 0 Cov.: 31 AF XY: 0.00000170 AC XY: 1 AN XY: 588012

⚠️ 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: 25756

American (AMR) AF: 0.00 AC: 0 AN: 39482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21834

East Asian (EAS) AF: 0.00 AC: 0 AN: 34292

South Asian (SAS) AF: 0.00 AC: 0 AN: 75306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4870

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 877122

Other (OTH) AF: 0.00 AC: 0 AN: 48638

⚠️ 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 Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HLA-DRB5: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.8
DANN	Benign	0.64
PhyloP100		1.2
PromoterAI		-0.0084	Neutral
Mutation Taster		=100/0	polymorphism

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: rs75457801; hg19: chr6-32497960; COSMIC: COSV66612956;