NM_003532.3:c.68C>T

Variant names:

• chr6-26225222-C-T
• rs1765602125
• NM_003532.3:c.68C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003532.3(H3C6):​c.68C>T​(p.Thr23Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T23S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: H3C6 NM_003532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

Genes affected

H3C6 (HGNC:4769): (H3 clustered histone 6) 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 large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]

ENSG00000291336 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003532.3. 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
	H3C6	NM_003532.3	MANE Select	c.68C>T	p.Thr23Ile	missense	Exon 1 of 1	NP_003523.1
	H3C6	NM_001381999.1		c.68C>T	p.Thr23Ile	missense	Exon 2 of 2	NP_001368928.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3C6	ENST00000614911.3	TSL:6 MANE Select	c.68C>T	p.Thr23Ile	missense	Exon 1 of 1	ENSP00000482271.1	P68431
	H3C6	ENST00000634733.1	TSL:1	c.68C>T	p.Thr23Ile	missense	Exon 2 of 2	ENSP00000489282.1	P68431
	H3C6	ENST00000876315.1		c.68C>T	p.Thr23Ile	missense	Exon 2 of 2	ENSP00000546374.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458158 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725322

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 85860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109946

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000475 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.83
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.64	T
PhyloP100		6.0
PrimateAI	Pathogenic	0.88	D
Sift4G	Uncertain	0.047	D
Vest4		0.52
MVP		0.11
ClinPred		0.54	D
GERP RS		4.5
PromoterAI		0.070	Neutral
gMVP		0.44
Mutation Taster		=73/27	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: rs1765602125; hg19: chr6-26225450;