rs1377460175

Variant names:

• chr6-32530170-G-A
• rs1377460175
• NM_002125.4:c.55C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_002125.4(HLA-DRB5):​c.55C>T​(p.Leu19Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 36)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DRB5 NM_002125.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.247
• Publications: 0 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-32530170-G-A is Benign according to our data. Variant chr6-32530170-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.247 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DRB5	NM_002125.4	c.55C>T	p.Leu19Leu	synonymous_variant	Exon 1 of 6	ENST00000374975.4	NP_002116.2
HLA-DRB5	XM_011514562.3	c.55C>T	p.Leu19Leu	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.55C>T	p.Leu19Leu	synonymous_variant	Exon 1 of 6	6	NM_002125.4	ENSP00000364114.3
HLA-DRB5	ENST00000714490.1	c.55C>T	p.Leu19Leu	synonymous_variant	Exon 1 of 6			ENSP00000519744.1

Frequencies

GnomAD3 genomes AF: 0.0000469 AC: 7 AN: 149296 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000405

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 228068 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000143 AC: 2 AN: 1398314 Hom.: 0 Cov.: 38 AF XY: 0.00000143 AC XY: 1 AN XY: 697808

⚠️ 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: 30898

American (AMR) AF: 0.00 AC: 0 AN: 43868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 37594

South Asian (SAS) AF: 0.00 AC: 0 AN: 83426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1061324

Other (OTH) AF: 0.00 AC: 0 AN: 57778

⚠️ 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: 0.0000468 AC: 7 AN: 149416 Hom.: 0 Cov.: 36 AF XY: 0.0000549 AC XY: 4 AN XY: 72914

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

African (AFR) AF: 0.0000736 AC: 3 AN: 40750

American (AMR) AF: 0.0000666 AC: 1 AN: 15008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.000406 AC: 2 AN: 4926

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67028

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ 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: 0.0168 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 01, 2023

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	7.2
DANN	Benign	0.76
PhyloP100		-0.25
PromoterAI		-0.13	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: rs1377460175; hg19: chr6-32497947; COSMIC: COSV66613904;