chr6-26156404-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_005321.3(H1-4):c.14C>T(p.Ala5Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000782 in 1,584,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

H1-4
NM_005321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.80

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 links:

ENSG00000291336 (HGNC:):

ENSG00000291336 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19747382).

BP6

Variant 6-26156404-C-T is Benign according to our data. Variant chr6-26156404-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2656299.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H1-4	NM_005321.3 link	c.14C>T	p.Ala5Val	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.14C>T	p.Ala5Val	missense_variant	Exon 1 of 1	6	NM_005321.3	ENSP00000307705.4		P10412
ENSG00000291336	ENST00000707189.1 link	n.999+32233C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000883

AC:

AN:

226394

AF XY:

0.000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000592

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000810

AC:

116

AN:

1432538

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

710318

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

AC:

AN:

32348

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

40626

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24662

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39314

Gnomad4 SAS exome

AF:

0.0000356

AC:

AN:

84218

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

49352

Gnomad4 NFE exome

AF:

0.0000966

AC:

106

AN:

1097612

Gnomad4 Remaining exome

AF:

0.000102

AC:

AN:

58956

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<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:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000241115

AN:

0.0000241115

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000206782

AN:

0.000206782

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000882

AC:

0.000088186

AN:

0.000088186

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.000199

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000994

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 20, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.061

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.79

M_CAP

Benign

0.042

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.38

Sift4G

Benign

0.13

Polyphen

0.74

Vest4

0.48

MutPred

0.22

Loss of glycosylation at P6 (P = 0.0636);

MVP

0.10

ClinPred

0.25

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.65

Mutation Taster

=62/38

polymorphism

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

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