NM_003519.4:c.11T>C

Variant names:

• chr6-27807896-A-G
• rs200484
• NM_003519.4:c.11T>C

Variant summary

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

The NM_003519.4(H2BC13):​c.11T>C​(p.Leu4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,976 control chromosomes in the GnomAD database, including 12,384 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.12 (1307 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11077 hom.)
• Consequence: H2BC13 NM_003519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48
• Publications: 49 publications found

Genes affected

H2BC13 (HGNC:4748): (H2B clustered histone 13) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the small histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015999079).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2BC13	NM_003519.4	c.11T>C	p.Leu4Pro	missense_variant	Exon 1 of 1	ENST00000377401.4	NP_003510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2BC13	ENST00000377401.4	c.11T>C	p.Leu4Pro	missense_variant	Exon 1 of 1	6	NM_003519.4	ENSP00000366618.2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18631 AN: 152020 Hom.: 1306 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0821

Gnomad SAS AF: 0.0764

Gnomad FIN AF: 0.0485

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0975

GnomAD2 exomes AF: 0.0983 AC: 24697 AN: 251350 AF XY: 0.0951

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.0793

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0863

GnomAD4 exome AF: 0.118 AC: 172086 AN: 1461838 Hom.: 11077 Cov.: 32 AF XY: 0.115 AC XY: 83460 AN XY: 727220

African (AFR) AF: 0.191 AC: 6388 AN: 33478

American (AMR) AF: 0.117 AC: 5233 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 966 AN: 26130

East Asian (EAS) AF: 0.0874 AC: 3471 AN: 39700

South Asian (SAS) AF: 0.0759 AC: 6547 AN: 86248

European-Finnish (FIN) AF: 0.0535 AC: 2860 AN: 53420

Middle Eastern (MID) AF: 0.0390 AC: 225 AN: 5768

European-Non Finnish (NFE) AF: 0.126 AC: 139971 AN: 1111990

Other (OTH) AF: 0.106 AC: 6425 AN: 60394

GnomAD4 genome AF: 0.123 AC: 18643 AN: 152138 Hom.: 1307 Cov.: 32 AF XY: 0.118 AC XY: 8764 AN XY: 74414

African (AFR) AF: 0.185 AC: 7674 AN: 41498

American (AMR) AF: 0.122 AC: 1868 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3470

East Asian (EAS) AF: 0.0821 AC: 424 AN: 5166

South Asian (SAS) AF: 0.0771 AC: 372 AN: 4826

European-Finnish (FIN) AF: 0.0485 AC: 515 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7329 AN: 67956

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.109 Hom.: 3829

Bravo AF: 0.131

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.189 AC: 831

ESP6500EA AF: 0.111 AC: 955

ExAC AF: 0.0990 AC: 12020

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.1
DANN	Benign	0.51
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.97	N
PhyloP100		3.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.093
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.67
ClinPred		0.020	T
GERP RS		4.3
PromoterAI		0.041	Neutral
Varity_R		0.086
gMVP		0.0093
Mutation Taster		=96/4	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: rs200484; hg19: chr6-27775674; COSMIC: COSV107441119; COSMIC: COSV107441119;