1-149887128-A-C

Variant names:

• chr1-149887128-A-C
• rs201477575
• NM_003517.3:c.154A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003517.3(H2AC20):​c.154A>C​(p.Met52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. M52V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: H2AC20 NM_003517.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950
• Publications: 3 publications found

Genes affected

H2AC20 (HGNC:4738): (H2A clustered histone 20) 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 H2A family. [provided by RefSeq, Aug 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03378457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003517.3. 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
	H2AC20	NM_003517.3	MANE Select	c.154A>C	p.Met52Leu	missense	Exon 1 of 1	NP_003508.1	Q16777

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	H2AC20	ENST00000331380.4	TSL:6 MANE Select	c.154A>C	p.Met52Leu	missense	Exon 1 of 1	ENSP00000332194.3	Q16777

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.62
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-0.095
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.67		Loss of catalytic residue at M52 (P = 0.021)
MVP		0.34
MPC		1.1
ClinPred		0.10	T
GERP RS		0.12
PromoterAI		-0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.79
Mutation Taster		=87/13	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: rs201477575; hg19: chr1-149858678; COSMIC: COSV58612995; COSMIC: COSV58612995;