Genetic Variant NM_003541.3:c.48T>A (chr6-27831480-A-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003541.3(H4C12):c.48T>A(p.Ala16Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0419 in 1,526,882 control chromosomes in the GnomAD database, including 1,248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 112 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1136 hom. )

Consequence

H4C12
NM_003541.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.439

Publications

6 publications found

Variant links:

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]

H4C12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 6-27831480-A-T is Benign according to our data. Variant chr6-27831480-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 774643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.439 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

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.48T>A	p.Ala16Ala	synonymous	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.48T>A	p.Ala16Ala	synonymous	Exon 1 of 1	ENSP00000479794.2	P62805
	H4C12	ENST00000718434.1		c.48T>A	p.Ala16Ala	synonymous	Exon 1 of 1	ENSP00000520819.1	P62805

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5101

AN:

152178

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00794

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.0221

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.0624

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0462

Gnomad OTH

AF:

0.0297

GnomAD2 exomes

AF:

0.0394

AC:

6684

AN:

169720

AF XY:

0.0418

show subpopulations

Gnomad AFR exome

AF:

0.00669

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0274

Gnomad EAS exome

AF:

0.0184

Gnomad FIN exome

AF:

0.0645

Gnomad NFE exome

AF:

0.0437

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0429

AC:

58945

AN:

1374586

Hom.:

1136

Cov.:

AF XY:

0.0440

AC XY:

29713

AN XY:

675500

show subpopulations

African (AFR)

AF:

0.00557

AC:

169

AN:

30332

American (AMR)

AF:

0.0160

AC:

468

AN:

29264

Ashkenazi Jewish (ASJ)

AF:

0.0273

AC:

544

AN:

19952

East Asian (EAS)

AF:

0.00899

AC:

352

AN:

39144

South Asian (SAS)

AF:

0.0755

AC:

5339

AN:

70728

European-Finnish (FIN)

AF:

0.0654

AC:

3270

AN:

49974

Middle Eastern (MID)

AF:

0.0182

AC:

AN:

5318

European-Non Finnish (NFE)

AF:

0.0433

AC:

46508

AN:

1073336

Other (OTH)

AF:

0.0389

AC:

2198

AN:

56538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

2624

5249

7873

10498

13122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1770

3540

5310

7080

8850

<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

AF:

0.0335

AC:

5096

AN:

152296

Hom.:

112

Cov.:

AF XY:

0.0346

AC XY:

2573

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00791

AC:

329

AN:

41582

American (AMR)

AF:

0.0201

AC:

307

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3472

East Asian (EAS)

AF:

0.0214

AC:

111

AN:

5180

South Asian (SAS)

AF:

0.0702

AC:

339

AN:

4828

European-Finnish (FIN)

AF:

0.0624

AC:

662

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0462

AC:

3139

AN:

68008

Other (OTH)

AF:

0.0294

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

230

459

689

918

1148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0370

Hom.:

Bravo

AF:

0.0279

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.1

(source)

DANN

Benign

0.51

PhyloP100

-0.44

PromoterAI

-0.017

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over