12-48329569-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181788.1(H1-7):​c.278A>T​(p.Lys93Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

H1-7
NM_181788.1 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.480
Variant links:
Genes affected
H1-7 (HGNC:24893): (H1.7 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 is intronless and encodes a replication-independent histone that is a member of the histone H1 family. The related mouse gene encodes a testis specific protein that is required for spermatogenesis and male fertility. [provided by RefSeq, Oct 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19988096).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H1-7NM_181788.1 linkc.278A>T p.Lys93Met missense_variant Exon 1 of 1 ENST00000335017.1 NP_861453.1 Q75WM6A0A140VK96

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H1-7ENST00000335017.1 linkc.278A>T p.Lys93Met missense_variant Exon 1 of 1 6 NM_181788.1 ENSP00000334805.1 Q75WM6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.278A>T (p.K93M) alteration is located in exon 1 (coding exon 1) of the H1FNT gene. This alteration results from a A to T substitution at nucleotide position 278, causing the lysine (K) at amino acid position 93 to be replaced by a methionine (M). 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
Uncertain
0.38
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T
Eigen
Benign
0.058
Eigen_PC
Benign
-0.084
FATHMM_MKL
Benign
0.62
D
LIST_S2
Benign
0.50
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-3.6
D
REVEL
Benign
0.050
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.011
D
Polyphen
1.0
D
Vest4
0.30
MutPred
0.27
Loss of solvent accessibility (P = 0.0187);
MVP
0.49
MPC
0.82
ClinPred
0.98
D
GERP RS
2.3
Varity_R
0.17
gMVP
0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48723352; API