NM_001376937.1:c.290G>C

Variant names:

• chr6-26196961-C-G
• rs1764983126
• NM_001376937.1:c.290G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001376937.1(H3C4):​c.290G>C​(p.Cys97Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. C97Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: H3C4 NM_001376937.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69
• Publications: 0 publications found

Genes affected

H3C4 (HGNC:4767): (H3 clustered histone 4) 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]

ENSG00000282988 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35013497).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376937.1. 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
	H3C4	NM_001376937.1	MANE Select	c.290G>C	p.Cys97Ser	missense	Exon 1 of 1	NP_001363866.1
	H3C4	NM_003530.4		c.290G>C	p.Cys97Ser	missense	Exon 2 of 2	NP_003521.2	P68431

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H3C4	ENST00000356476.3	TSL:6 MANE Select	c.290G>C	p.Cys97Ser	missense	Exon 1 of 1	ENSP00000366999.2	P68431
	ENSG00000282988	ENST00000635200.1	TSL:3	c.*181G>C		3_prime_UTR	Exon 2 of 2	ENSP00000489311.1	A0A0U1RR32
	H3C4	ENST00000718271.1		c.290G>C	p.Cys97Ser	missense	Exon 1 of 1	ENSP00000520711.1	P68431

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461752 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.92
Eigen	Benign	0.00048
Eigen_PC	Benign	0.052
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.095
Sift4G	Benign	1.0	T
Vest4		0.21
MutPred		0.48		Gain of disorder (P = 0.0096)
MVP		0.36
ClinPred		0.56	D
GERP RS		3.4
PromoterAI		-0.00030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20
Mutation Taster		=41/59	disease causing

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: rs1764983126; hg19: chr6-26197189;