6-32949767-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006120.4(HLA-DMA):​c.496G>A​(p.Val166Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,612,842 control chromosomes in the GnomAD database, including 15,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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: 𝑓 0.13 (1507 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14046 hom.)
• Consequence: HLA-DMA NM_006120.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.260
• Publications: 51 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004783809).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

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>A	p.Val166Ile	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>A	p.Val166Ile	missense	Exon 3 of 5	ENSP00000363976.4	P28067
	ENSG00000248993	ENST00000429234.1	TSL:2	c.88+3182G>A		intron	N/A	ENSP00000412457.1	F6UB75
	HLA-DMA	ENST00000456800.1	TSL:6	c.586G>A	p.Val196Ile	missense	Exon 3 of 4	ENSP00000409668.1	H0Y732

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20144 AN: 152040 Hom.: 1498 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.150 AC: 36873 AN: 246218 AF XY: 0.154

Gnomad AFR exome AF: 0.0991

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.0970

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.131 AC: 191990 AN: 1460684 Hom.: 14046 Cov.: 35 AF XY: 0.134 AC XY: 97331 AN XY: 726652

African (AFR) AF: 0.110 AC: 3686 AN: 33480

American (AMR) AF: 0.177 AC: 7925 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4514 AN: 26134

East Asian (EAS) AF: 0.199 AC: 7904 AN: 39698

South Asian (SAS) AF: 0.219 AC: 18902 AN: 86254

European-Finnish (FIN) AF: 0.0976 AC: 5104 AN: 52310

Middle Eastern (MID) AF: 0.161 AC: 927 AN: 5768

European-Non Finnish (NFE) AF: 0.121 AC: 134028 AN: 1111932

Other (OTH) AF: 0.149 AC: 9000 AN: 60384

GnomAD4 genome AF: 0.132 AC: 20151 AN: 152158 Hom.: 1507 Cov.: 32 AF XY: 0.135 AC XY: 10034 AN XY: 74380

African (AFR) AF: 0.101 AC: 4211 AN: 41498

American (AMR) AF: 0.194 AC: 2969 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3472

East Asian (EAS) AF: 0.253 AC: 1309 AN: 5178

South Asian (SAS) AF: 0.224 AC: 1081 AN: 4826

European-Finnish (FIN) AF: 0.101 AC: 1064 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8364 AN: 68004

Other (OTH) AF: 0.150 AC: 317 AN: 2110

Alfa AF: 0.129 Hom.: 3661

Bravo AF: 0.136

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.123 AC: 475

ESP6500AA AF: 0.0936 AC: 283

ESP6500EA AF: 0.128 AC: 696

ExAC AF: 0.145 AC: 17132

Asia WGS AF: 0.250 AC: 867 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.73
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.037	N
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.26
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.010
Sift	Benign	0.40	T
Sift4G	Benign	0.22	T
Vest4		0.091
MPC		0.32
ClinPred		0.00074	T
GERP RS		1.5
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

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: rs1063478; hg19: chr6-32917544; COSMIC: COSV104690176; COSMIC: COSV104690176;