chr6-27831413-C-G

Variant names:

• chr6-27831413-C-G
• rs781178850
• NM_003541.3:c.115G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003541.3(H4C12):​c.115G>C​(p.Ala39Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: H4C12 NM_003541.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04
• Publications: 0 publications found

Genes affected

H4C12 (HGNC:4784): (H4 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 H4 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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003541.3. 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
	H4C12	NM_003541.3	MANE Select	c.115G>C	p.Ala39Pro	missense	Exon 1 of 1	NP_003532.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H4C12	ENST00000611927.2	TSL:6 MANE Select	c.115G>C	p.Ala39Pro	missense	Exon 1 of 1	ENSP00000479794.2	P62805
	H4C12	ENST00000718434.1		c.115G>C	p.Ala39Pro	missense	Exon 1 of 1	ENSP00000520819.1	P62805

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000491 AC: 1 AN: 203652 AF XY: 0.00000897

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435838 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 711096

African (AFR) AF: 0.00 AC: 0 AN: 32680

American (AMR) AF: 0.00 AC: 0 AN: 41486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24606

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096570

Other (OTH) AF: 0.00 AC: 0 AN: 58982

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000837 AC: 1

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	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.29	T
PhyloP100		7.0
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.010	D
Vest4		0.90
MVP		0.10
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.029	Neutral
gMVP		0.50
Mutation Taster		=44/56	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: rs781178850; hg19: chr6-27799191;