Genetic Variant H1-3:p.Lys214Arg (chr6-26234293-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005320.3(H1-3):c.641A>G(p.Lys214Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,602,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

H1-3
NM_005320.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.74

Variant links:

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]

H1-3 links:

ENSG00000291336 (HGNC:):

ENSG00000291336 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H1-3	NM_005320.3 link	c.641A>G	p.Lys214Arg	missense_variant	Exon 1 of 1	ENST00000244534.7	NP_005311.1	P16402

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
H1-3	ENST00000244534.7 link	c.641A>G	p.Lys214Arg	missense_variant	Exon 1 of 1	6	NM_005320.3	ENSP00000244534.6	P16402
ENSG00000291336	ENST00000707189.1 link	n.999+110122T>C		intron_variant	Intron 1 of 1
ENSG00000291338	ENST00000707191.1 link	n.1000+76172T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000583

AC:

AN:

240030

Hom.:

AF XY:

0.0000461

AC XY:

AN XY:

130114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.0000641

AC:

AN:

1450494

Hom.:

Cov.:

AF XY:

0.0000693

AC XY:

AN XY:

721620

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000767

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.641A>G (p.K214R) alteration is located in exon 1 (coding exon 1) of the HIST1H1D gene. This alteration results from a A to G substitution at nucleotide position 641, causing the lysine (K) at amino acid position 214 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.24

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.42

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.69

REVEL

Benign

0.24

Sift

Benign

0.67

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.49

MVP

0.48

ClinPred

0.81

GERP RS

5.1

Varity_R

0.17

gMVP

0.0032

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over