NM_003535.3:c.382G>T

Variant names:

• chr6-27890411-C-A
• NM_003535.3:c.382G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003535.3(H3C12):​c.382G>T​(p.Ala128Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A128T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: H3C12 NM_003535.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64

Genes affected

H3C12 (HGNC:4774): (H3 clustered histone 12) 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 is intronless and encodes a replication-dependent histone that is a member of the histone H3 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the small histone gene cluster on chromosome 6p22-p21.3. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3C12	NM_003535.3	c.382G>T	p.Ala128Ser	missense_variant	Exon 1 of 1	ENST00000359303.4	NP_003526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3C12	ENST00000359303.4	c.382G>T	p.Ala128Ser	missense_variant	Exon 1 of 1	6	NM_003535.3	ENSP00000352252.3
H3C12	ENST00000479986.1	n.*224G>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443258 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.12	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.63
Sift4G	Uncertain	0.0080	D
Vest4		0.70
MutPred		0.75		Gain of disorder (P = 0.0286);
MVP		0.84
MPC		1.3
ClinPred		0.97	D
GERP RS		4.1
gMVP		0.22

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: chr6-27858189;