6-27139614-C-T

Variant names:

• chr6-27139614-C-T
• rs61742445
• NM_003495.3:c.306C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_003495.3(H4C9):​c.306C>T​(p.Gly102Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00764 in 1,607,340 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (60 hom.)
• Consequence: H4C9 NM_003495.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.467

Genes affected

H4C9 (HGNC:4793): (H4 clustered histone 9) 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 histone microcluster on chromosome 6p21.33. [provided by RefSeq, Aug 2015]

H2BC12 (HGNC:13954): (H2B 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 encodes a replication-dependent histone that is a member of the histone H2B family. The protein encoded is an antimicrobial protein with antibacterial and antifungal activity. Two transcripts that encode the same protein have been identified for this gene, which is found in the histone microcluster on chromosome 6p21.33. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-27139614-C-T is Benign according to our data. Variant chr6-27139614-C-T is described in ClinVar as [Benign]. Clinvar id is 780599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.467 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1971/152318) while in subpopulation AFR AF= 0.0316 (1312/41578). AF 95% confidence interval is 0.0301. There are 25 homozygotes in gnomad4. There are 887 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1971 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H4C9	NM_003495.3	c.306C>T	p.Gly102Gly	synonymous_variant	Exon 1 of 1	ENST00000615353.2	NP_003486.1
H2BC12	NM_080593.2	c.*10-933G>A		intron_variant	Intron 1 of 1		NP_542160.1
H2BC12	XR_007059350.1	n.884-933G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H4C9	ENST00000615353.2	c.306C>T	p.Gly102Gly	synonymous_variant	Exon 1 of 1	6	NM_003495.3	ENSP00000481486.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1972 AN: 152200 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00661 AC: 1617 AN: 244578 Hom.: 18 AF XY: 0.00580 AC XY: 767 AN XY: 132128

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00826

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00137

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00784

GnomAD4 exome AF: 0.00709 AC: 10312 AN: 1455022 Hom.: 60 Cov.: 30 AF XY: 0.00673 AC XY: 4867 AN XY: 723362

Gnomad4 AFR exome AF: 0.0320

Gnomad4 AMR exome AF: 0.00961

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00188

Gnomad4 NFE exome AF: 0.00718

Gnomad4 OTH exome AF: 0.00773

GnomAD4 genome AF: 0.0129 AC: 1971 AN: 152318 Hom.: 25 Cov.: 32 AF XY: 0.0119 AC XY: 887 AN XY: 74476

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00773 Hom.: 6

Bravo AF: 0.0148

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.4
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs61742445; hg19: chr6-27107393; COSMIC: COSV62890085; COSMIC: COSV62890085;