Genetic Variant H1-10:p.Ala136Thr (chr3-129315497-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006026.4(H1-10):c.406G>A(p.Ala136Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,377,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A136P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

H1-10
NM_006026.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.592

Variant links:

Genes affected

H1-10 (HGNC:4722): (H1.10 linker histone) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a replication-independent histone that is a member of the histone H1 family. [provided by RefSeq, Oct 2015]

H1-10 links:

H1-10-AS1 (HGNC:27953): (H1-10 antisense RNA 1)

H1-10-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057418466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H1-10	NM_006026.4 link	c.406G>A	p.Ala136Thr	missense_variant	Exon 1 of 1	ENST00000333762.6	NP_006017.1	Q92522

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
H1-10	ENST00000333762.6 link	c.406G>A	p.Ala136Thr	missense_variant	Exon 1 of 1	6	NM_006026.4	ENSP00000329662.4	Q92522
H1-10	ENST00000704995.1 link	c.559G>A	p.Ala187Thr	missense_variant	Exon 1 of 1			ENSP00000516065.1	A0A994J4R3
H1-10-AS1	ENST00000511998.1 link	n.106C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5
H1-10-AS1	ENST00000433902.2 link	n.-23C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000155

AC:

AN:

128682

Hom.:

AF XY:

0.0000283

AC XY:

AN XY:

70666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000201

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000436

AC:

AN:

1377060

Hom.:

Cov.:

AF XY:

0.00000589

AC XY:

AN XY:

679026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000854

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406G>A (p.A136T) alteration is located in exon 1 (coding exon 1) of the H1FX gene. This alteration results from a G to A substitution at nucleotide position 406, causing the alanine (A) at amino acid position 136 to be replaced by a threonine (T). 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

0.065

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.084

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.53

M_CAP

Benign

0.019

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.24

REVEL

Benign

0.011

Sift

Benign

0.22

Sift4G

Benign

0.37

Polyphen

0.0080

Vest4

0.098

MutPred

0.20

Gain of glycosylation at A136 (P = 8e-04);

MVP

0.040

MPC

0.62

ClinPred

0.046

GERP RS

0.48

Varity_R

0.17

gMVP

0.18

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