10-70109173-A-C

Variant names:

• chr10-70109173-A-C
• NM_018649.3:c.919A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018649.3(MACROH2A2):​c.919A>C​(p.Lys307Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACROH2A2 NM_018649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

MACROH2A2 (HGNC:14453): (macroH2A.2 histone) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a replication-independent histone that is a member of the histone H2A family. It replaces conventional H2A histones in a subset of nucleosomes where it represses transcription and may participate in stable X chromosome inactivation. [provided by RefSeq, Oct 2015]

AIFM2 (HGNC:21411): (apoptosis inducing factor mitochondria associated 2) This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACROH2A2	NM_018649.3	c.919A>C	p.Lys307Gln	missense_variant	Exon 8 of 9	ENST00000373255.9	NP_061119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACROH2A2	ENST00000373255.9	c.919A>C	p.Lys307Gln	missense_variant	Exon 8 of 9	1	NM_018649.3	ENSP00000362352.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.919A>C (p.K307Q) alteration is located in exon 8 (coding exon 7) of the H2AFY2 gene. This alteration results from a A to C substitution at nucleotide position 919, causing the lysine (K) at amino acid position 307 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.0049	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	D;.
Vest4		0.66
MutPred		0.55		Loss of ubiquitination at K307 (P = 0.0199);.;
MVP		0.40
MPC		1.6
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.75
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-71868929;