6-32949767-C-G

Variant names:

• chr6-32949767-C-G
• rs1063478
• NM_006120.4:c.496G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006120.4(HLA-DMA):​c.496G>C​(p.Val166Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HLA-DMA NM_006120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 0 publications found

Genes affected

HLA-DMA (HGNC:4934): (major histocompatibility complex, class II, DM alpha) HLA-DMA belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DMA) and a beta chain (DMB), 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 molecule from the peptide binding site. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and the cytoplasmic tail. [provided by RefSeq, Jul 2008]

ENSG00000248993 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061172366).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006120.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DMA	NM_006120.4	MANE Select	c.496G>C	p.Val166Leu	missense	Exon 3 of 5	NP_006111.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DMA	ENST00000374843.9	TSL:6 MANE Select	c.496G>C	p.Val166Leu	missense	Exon 3 of 5	ENSP00000363976.4	P28067
	ENSG00000248993	ENST00000429234.1	TSL:2	c.88+3182G>C		intron	N/A	ENSP00000412457.1	F6UB75
	HLA-DMA	ENST00000456800.1	TSL:6	c.586G>C	p.Val196Leu	missense	Exon 3 of 4	ENSP00000409668.1	H0Y732

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460762 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726692

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.33
DANN	Benign	0.87
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.057	N
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.26
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.0060
Sift	Benign	0.18	T
Sift4G	Benign	0.30	T
Vest4		0.19
MutPred		0.24		Gain of sheet (P = 0.1451)
MVP		0.068
MPC		0.39
ClinPred		0.037	T
GERP RS		1.5
gMVP		0.18
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1063478; hg19: chr6-32917544;