chr6-26234288-C-G

Variant names:

• chr6-26234288-C-G
• rs202225825
• NM_005320.3:c.646G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005320.3(H1-3):​c.646G>C​(p.Ala216Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,596,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A216G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: H1-3 NM_005320.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.836
• Publications: 0 publications found

Genes affected

H1-3 (HGNC:4717): (H1.3 linker histone, cluster member) Histones are basic nuclear proteins responsible for 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 H1 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]

ENSG00000291336 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04900953).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005320.3. 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
	H1-3	NM_005320.3	MANE Select	c.646G>C	p.Ala216Pro	missense	Exon 1 of 1	NP_005311.1	P16402

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H1-3	ENST00000244534.7	TSL:6 MANE Select	c.646G>C	p.Ala216Pro	missense	Exon 1 of 1	ENSP00000244534.6	P16402
	ENSG00000291336	ENST00000707189.1		n.999+110117C>G		intron	N/A
	ENSG00000291338	ENST00000707191.1		n.1000+76167C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000273 AC: 64 AN: 234494 AF XY: 0.000196

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.000123 AC: 177 AN: 1444392 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 87 AN XY: 718412

African (AFR) AF: 0.0000313 AC: 1 AN: 31938

American (AMR) AF: 0.00120 AC: 47 AN: 39170

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25224

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 83220

European-Finnish (FIN) AF: 0.0000565 AC: 3 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.000106 AC: 117 AN: 1106960

Other (OTH) AF: 0.000134 AC: 8 AN: 59546

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74368

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.000458 AC: 7 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.84
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.071	T
Polyphen		0.0020	B
Vest4		0.44
MVP		0.17
ClinPred		0.19	T
GERP RS		1.3
Varity_R		0.68
gMVP		0.025
Mutation Taster		=68/32	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: rs202225825; hg19: chr6-26234516;