6-27831413-C-T

Variant names:

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

Variant summary

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

The NM_003541.3(H4C12):​c.115G>A​(p.Ala39Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,435,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A39P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: H4C12 NM_003541.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

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

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>A	p.Ala39Thr	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>A	p.Ala39Thr	missense	Exon 1 of 1	ENSP00000479794.2	P62805
	H4C12	ENST00000718434.1		c.115G>A	p.Ala39Thr	missense	Exon 1 of 1	ENSP00000520819.1	P62805

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1435838 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 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: 0.00000274 AC: 3 AN: 1096570

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.20	T
PhyloP100		7.0
PrimateAI	Uncertain	0.78	T
Sift4G	Uncertain	0.0090	D
Vest4		0.74
MVP		0.072
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		-0.034	Neutral
gMVP		0.12
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;