NM_005321.3:c.455A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005321.3(H1-4):c.455A>G(p.Lys152Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00909 in 1,607,174 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K152Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0063 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 102 hom. )

Consequence

H1-4
NM_005321.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.97

Publications

15 publications found

Variant links:

Genes affected

H1-4 (HGNC:4718): (H1.4 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]

H1-4 Gene-Disease associations (from GenCC):

Rahman syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

H1-4 links:

ENSG00000291336 (HGNC:):

ENSG00000291336 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008633345).

BP6

Variant 6-26156845-A-G is Benign according to our data. Variant chr6-26156845-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 773469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00631 (961/152346) while in subpopulation EAS AF = 0.0112 (58/5172). AF 95% confidence interval is 0.00892. There are 4 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 961 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H1-4	NM_005321.3 link	c.455A>G	p.Lys152Arg	missense_variant	Exon 1 of 1	ENST00000304218.6	NP_005312.1	P10412A3R0T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H1-4	ENST00000304218.6 link	c.455A>G	p.Lys152Arg	missense_variant	Exon 1 of 1	6	NM_005321.3	ENSP00000307705.4		P10412
ENSG00000291336	ENST00000707189.1 link	n.999+32674A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00631

AC:

960

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.00602

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00952

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00772

AC:

1814

AN:

234858

AF XY:

0.00845

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.00232

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00841

Gnomad FIN exome

AF:

0.00913

Gnomad NFE exome

AF:

0.00942

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.00938

AC:

13642

AN:

1454828

Hom.:

102

Cov.:

AF XY:

0.00957

AC XY:

6927

AN XY:

723570

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

32954

American (AMR)

AF:

0.00271

AC:

117

AN:

43134

Ashkenazi Jewish (ASJ)

AF:

0.0000768

AC:

AN:

26030

East Asian (EAS)

AF:

0.0215

AC:

850

AN:

39458

South Asian (SAS)

AF:

0.0126

AC:

1082

AN:

85810

European-Finnish (FIN)

AF:

0.00982

AC:

520

AN:

52980

Middle Eastern (MID)

AF:

0.00420

AC:

AN:

5242

European-Non Finnish (NFE)

AF:

0.00957

AC:

10621

AN:

1109250

Other (OTH)

AF:

0.00654

AC:

392

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

888

1776

2663

3551

4439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

406

812

1218

1624

2030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00631

AC:

961

AN:

152346

Hom.:

Cov.:

AF XY:

0.00621

AC XY:

463

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41590

American (AMR)

AF:

0.00392

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0112

AC:

AN:

5172

South Asian (SAS)

AF:

0.0104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00602

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00953

AC:

648

AN:

68028

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

190

238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00804

Hom.:

Bravo

AF:

0.00556

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.000914

AC:

ESP6500EA

AF:

0.00770

AC:

ExAC

AF:

0.00749

AC:

905

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

H1-4: BS1, BS2 -

Aug 13, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26199320, 25937444) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.1

PhyloP100

9.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.85

REVEL

Benign

0.17

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.98

Vest4

0.51

MVP

0.29

ClinPred

0.16

GERP RS

5.5

Varity_R

0.24

gMVP

0.058

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over