6-32949767-C-T

Position:

• chr6-32949767-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-DMA	NM_006120.4	c.496G>A	p.Val166Ile	missense_variant	3/5	ENST00000374843.9	NP_006111.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-DMA	ENST00000374843.9	c.496G>A	p.Val166Ile	missense_variant	3/5	6	NM_006120.4	ENSP00000363976.4
ENSG00000248993	ENST00000429234.1	c.88+3182G>A		intron_variant		2		ENSP00000412457.1

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

GnomAD3 exomes AF: 0.150 AC: 36873 AN: 246218 Hom.: 3193 AF XY: 0.154 AC XY: 20648 AN XY: 134208

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 SAS exome AF: 0.221

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

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.0976

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.149

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

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.150

Alfa AF: 0.133 Hom.: 2493

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 v4.3

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;T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.037	N
MetaRNN	Benign	0.0048	T;T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.58	N;N;N;N;N
REVEL	Benign	0.010
Sift	Benign	0.40	T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;.;T
Vest4		0.091
MPC		0.32
ClinPred		0.00074	T
GERP RS		1.5
gMVP		0.10

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

Publications

LitVar

Other links and lift over

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