chr6-27139614-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1971 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003495.3. 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
	H4C9	NM_003495.3	MANE Select	c.306C>T	p.Gly102Gly	synonymous	Exon 1 of 1	NP_003486.1
	H2BC12	NM_080593.2		c.*10-933G>A		intron	N/A	NP_542160.1	O60814

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H4C9	ENST00000615353.2	TSL:6 MANE Select	c.306C>T	p.Gly102Gly	synonymous	Exon 1 of 1	ENSP00000481486.1	P62805
	H4C9	ENST00000715894.1		c.306C>T	p.Gly102Gly	synonymous	Exon 1 of 1	ENSP00000520530.1	P62805
	H2BC12	ENST00000715895.1		c.*10-933G>A		intron	N/A	ENSP00000520531.1	O60814

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

GnomAD2 exomes AF: 0.00661 AC: 1617 AN: 244578 AF XY: 0.00580

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 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

African (AFR) AF: 0.0320 AC: 1063 AN: 33238

American (AMR) AF: 0.00961 AC: 421 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 282 AN: 25532

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85422

European-Finnish (FIN) AF: 0.00188 AC: 100 AN: 53090

Middle Eastern (MID) AF: 0.00299 AC: 17 AN: 5688

European-Non Finnish (NFE) AF: 0.00718 AC: 7956 AN: 1108564

Other (OTH) AF: 0.00773 AC: 464 AN: 60024

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

African (AFR) AF: 0.0316 AC: 1312 AN: 41578

American (AMR) AF: 0.00882 AC: 135 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.00818 Hom.: 8

Bravo AF: 0.0148

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.4
DANN	Benign	0.91
PhyloP100		-0.47
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs61742445; hg19: chr6-27107393; COSMIC: COSV62890085; COSMIC: COSV62890085;