rs1057519903

Positions:

• chr1-226064434-A-G
• chr1-226064434-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 7P and 2B. PM1 PM2 PM5 PP2 BP4_Moderate

The NM_002107.7(H3-3A):​c.83A>G​(p.Lys28Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. K28M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: H3-3A NM_002107.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

Genes affected

H3-3A (HGNC:4764): (H3.3 histone A) Histones are basic nuclear proteins that are responsible for the 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 contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue N6-lactoyllysine; alternate (size 0) in uniprot entity H33_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-226064434-A-T is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), H3-3A. . Gene score misZ 3.1568 (greater than the threshold 3.09). GenCC has associacion of gene with Bryant-Li-Bhoj neurodevelopmental syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25037754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
H3-3A	NM_002107.7	c.83A>G	p.Lys28Arg	missense_variant	2/4	ENST00000366815.10	NP_002098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
H3-3A	ENST00000366815.10	c.83A>G	p.Lys28Arg	missense_variant	2/4	1	NM_002107.7	ENSP00000355780	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;.;D;.
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.6	M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0070	.;.;D;.
Sift4G	Benign	0.098	T;T;T;T
Polyphen		0.0030	B;B;D;B
Vest4		0.42
MutPred		0.24		Loss of ubiquitination at K28 (P = 0.0381);Loss of ubiquitination at K28 (P = 0.0381);Loss of ubiquitination at K28 (P = 0.0381);Loss of ubiquitination at K28 (P = 0.0381);
MVP		0.82
MPC		1.8
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.97
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-226252135; COSMIC: COSV64731769; COSMIC: COSV64731769;