Genetic Variant NM_005321.3:c.11C>G (chr6-26156401-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005321.3(H1-4):c.11C>G(p.Thr4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,431,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

H1-4
NM_005321.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.718

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20751727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005321.3. 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
	H1-4	NM_005321.3	MANE Select	c.11C>G	p.Thr4Ser	missense	Exon 1 of 1	NP_005312.1	P10412

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H1-4	ENST00000304218.6	TSL:6 MANE Select	c.11C>G	p.Thr4Ser	missense	Exon 1 of 1	ENSP00000307705.4	P10412
	ENSG00000291336	ENST00000707189.1		n.999+32230C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1431660

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709834

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32344

American (AMR)

AF:

0.00

AC:

AN:

40634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24572

East Asian (EAS)

AF:

0.00

AC:

AN:

39308

South Asian (SAS)

AF:

0.00

AC:

AN:

84090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5418

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097118

Other (OTH)

AF:

0.00

AC:

AN:

58922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.70

M_CAP

Benign

0.032

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.8

PhyloP100

0.72

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.16

Sift

Benign

0.12

Sift4G

Benign

0.24

Polyphen

0.68

Vest4

0.43

MutPred

0.16

Loss of glycosylation at S2 (P = 0.1238)

MVP

0.081

ClinPred

0.92

GERP RS

5.6

PromoterAI

-0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.52

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over