Genetic Variant NM_001376937.1:c.290G>A (chr6-26196961-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001376937.1(H3C4):c.290G>A(p.Cys97Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

H3C4
NM_001376937.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.69

Publications

0 publications found

Variant links:

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]

H3C4 links:

ENSG00000282988 (HGNC:):

ENSG00000282988 links:

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ACMG classification

Classification was made for transcript

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_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>A	p.Cys97Tyr	missense	Exon 1 of 1	NP_001363866.1
	H3C4	NM_003530.4		c.290G>A	p.Cys97Tyr	missense	Exon 2 of 2	NP_003521.2	P68431

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
H3C4	ENST00000356476.3	TSL:6 MANE Select	c.290G>A	p.Cys97Tyr	missense	Exon 1 of 1	ENSP00000366999.2	P68431
ENSG00000282988	ENST00000635200.1	TSL:3	c.*181G>A		3_prime_UTR	Exon 2 of 2	ENSP00000489311.1	A0A0U1RR32
H3C4	ENST00000718271.1		c.290G>A	p.Cys97Tyr	missense	Exon 1 of 1	ENSP00000520711.1	P68431

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0046

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.97

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.57

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.39

PhyloP100

4.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.20

Sift4G

Pathogenic

0.0010

Vest4

0.53

MutPred

0.42

Loss of catalytic residue at A92 (P = 0.1793)

MVP

0.47

ClinPred

0.92

GERP RS

3.4

PromoterAI

0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.49

Mutation Taster

=46/54

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over