Genetic Variant NM_002118.5:c.338-578T>C (chr6-32938034-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002118.5(HLA-DMB):c.338-578T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0624 in 153,212 control chromosomes in the GnomAD database, including 319 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 0.062 ( 315 hom., cov: 32)

Exomes 𝑓: 0.048 ( 4 hom. )

Consequence

HLA-DMB
NM_002118.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.282

Publications

29 publications found

Variant links:

Genes affected

HLA-DMB (HGNC:4935): (major histocompatibility complex, class II, DM beta) HLA-DMB belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DMA) and a beta (DMB) chain, both anchored in the membrane. It is located in intracellular vesicles. DM plays a central role in the peptide loading of MHC class II molecules by helping to release the CLIP (class II-associated invariant chain peptide) molecule from the peptide binding site. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). 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. [provided by RefSeq, Jul 2008]

HLA-DMB links:

ENSG00000248993 (HGNC:):

ENSG00000248993 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DMB	NM_002118.5 link	c.338-578T>C		intron_variant	Intron 2 of 5	ENST00000418107.3	NP_002109.2	P28068A0A1V0E3P2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HLA-DMB	ENST00000418107.3 link	c.338-578T>C	intron_variant	Intron 2 of 5	6	NM_002118.5	ENSP00000398890.2	P28068
ENSG00000248993	ENST00000429234.1 link	c.434-578T>C	intron_variant	Intron 3 of 3	2		ENSP00000412457.1	F6UB75
HLA-DMB	ENST00000498020.1 link	n.1164T>C	non_coding_transcript_exon_variant	Exon 2 of 2	6
HLA-DMB	ENST00000414017.5 link	c.5-578T>C	intron_variant	Intron 1 of 3	6		ENSP00000411276.1	H0Y7A2

Frequencies

GnomAD3 genomes

AF:

0.0625

AC:

9508

AN:

152118

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0854

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0536

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00500

Gnomad SAS

AF:

0.0442

Gnomad FIN

AF:

0.0447

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0614

Gnomad OTH

AF:

0.0593

GnomAD4 exome

AF:

0.0482

AC:

AN:

976

Hom.:

Cov.:

AF XY:

0.0508

AC XY:

AN XY:

492

show subpopulations

African (AFR)

AF:

0.0714

AC:

AN:

American (AMR)

AF:

0.0208

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0596

AC:

AN:

722

Other (OTH)

AF:

0.0217

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0625

AC:

9511

AN:

152236

Hom.:

315

Cov.:

AF XY:

0.0615

AC XY:

4577

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0853

AC:

3540

AN:

41510

American (AMR)

AF:

0.0536

AC:

820

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3470

East Asian (EAS)

AF:

0.00502

AC:

AN:

5184

South Asian (SAS)

AF:

0.0444

AC:

214

AN:

4820

European-Finnish (FIN)

AF:

0.0447

AC:

474

AN:

10610

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0614

AC:

4178

AN:

68018

Other (OTH)

AF:

0.0582

AC:

123

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

459

918

1376

1835

2294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0574

Hom.:

779

Bravo

AF:

0.0634

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.7

(source)

DANN

Benign

0.82

PhyloP100

-0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over