6-27890411-C-A

Variant names:

• chr6-27890411-C-A
• rs771701828
• NM_003535.3:c.382G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

ENSG00000305786 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003535.3. 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
	H3C12	NM_003535.3	MANE Select	c.382G>T	p.Ala128Ser	missense	Exon 1 of 1	NP_003526.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3C12	ENST00000359303.4	TSL:6 MANE Select	c.382G>T	p.Ala128Ser	missense	Exon 1 of 1	ENSP00000352252.3	P68431
	ENSG00000305786	ENST00000812940.1		n.195-2323G>T		intron	N/A
	H3C12	ENST00000479986.1	TSL:2	n.*224G>T		downstream_gene	N/A

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

African (AFR) AF: 0.00 AC: 0 AN: 32802

American (AMR) AF: 0.00 AC: 0 AN: 42414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 84924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100460

Other (OTH) AF: 0.00 AC: 0 AN: 59410

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.6
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
PromoterAI		-0.00040	Neutral
gMVP		0.22
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs771701828; hg19: chr6-27858189;