rs41553715

Variant names:

• chr6-31356732-T-A
• rs41553715
• NM_005514.8:c.299A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-31356732-T-A
• chr6-31356732-T-C
• chr6-31356732-T-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005514.8(HLA-B):​c.299A>T​(p.Glu100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.00073 (2 hom., cov: 7)
  • Exomes 𝑓: 0.0079 (157 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-B NM_005514.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.33
• Publications: 21 publications found

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

ENSG00000271581 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026462972).
• BS2: High AC in GnomAd4 at 42 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. 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-B	NM_005514.8	MANE Select	c.299A>T	p.Glu100Val	missense	Exon 2 of 8	NP_005505.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.299A>T	p.Glu100Val	missense	Exon 2 of 8	ENSP00000399168.2
	HLA-B	ENST00000696559.1		c.299A>T	p.Glu100Val	missense	Exon 5 of 11	ENSP00000512717.1
	HLA-B	ENST00000696560.1		c.299A>T	p.Glu100Val	missense	Exon 4 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes AF: 0.000732 AC: 42 AN: 57406 Hom.: 2 Cov.: 7

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000635

Gnomad EAS AF: 0.00527

Gnomad SAS AF: 0.00107

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0122

Gnomad NFE AF: 0.000534

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.0133 AC: 2756 AN: 207848 AF XY: 0.0123

Gnomad AFR exome AF: 0.00359

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.00399

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.0120

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00792 AC: 7851 AN: 991846 Hom.: 157 Cov.: 24 AF XY: 0.00806 AC XY: 3967 AN XY: 492354

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

African (AFR) AF: 0.00926 AC: 177 AN: 19122

American (AMR) AF: 0.00837 AC: 252 AN: 30100

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 82 AN: 18048

East Asian (EAS) AF: 0.0296 AC: 670 AN: 22600

South Asian (SAS) AF: 0.0119 AC: 632 AN: 53190

European-Finnish (FIN) AF: 0.00257 AC: 85 AN: 33082

Middle Eastern (MID) AF: 0.0143 AC: 43 AN: 3010

European-Non Finnish (NFE) AF: 0.00724 AC: 5594 AN: 772494

Other (OTH) AF: 0.00786 AC: 316 AN: 40200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000731 AC: 42 AN: 57464 Hom.: 2 Cov.: 7 AF XY: 0.000906 AC XY: 25 AN XY: 27588

African (AFR) AF: 0.000601 AC: 9 AN: 14968

American (AMR) AF: 0.000784 AC: 4 AN: 5100

Ashkenazi Jewish (ASJ) AF: 0.000635 AC: 1 AN: 1574

East Asian (EAS) AF: 0.00529 AC: 8 AN: 1512

South Asian (SAS) AF: 0.00106 AC: 1 AN: 940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4162

Middle Eastern (MID) AF: 0.0132 AC: 1 AN: 76

European-Non Finnish (NFE) AF: 0.000534 AC: 15 AN: 28088

Other (OTH) AF: 0.00419 AC: 3 AN: 716

Alfa AF: 0.00763 Hom.: 11

ExAC AF: 0.0162 AC: 1946

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.5
DANN	Benign	0.48
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.010	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
PhyloP100		-4.3
PROVEAN	Benign	2.9	N
REVEL	Uncertain	0.32
Sift	Benign	0.29	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.26
ClinPred		0.0079	T
GERP RS		-3.1
PromoterAI		-0.0033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.15
Mutation Taster		=100/0	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: rs41553715; hg19: chr6-31324509; COSMIC: COSV69520423; COSMIC: COSV69520423;