X-37991111-A-G

Position:

• chrX-37991111-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012274.2(H2AP):​c.272A>G​(p.Asn91Ser) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: H2AP NM_012274.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.943

Genes affected

H2AP (HGNC:18417): (H2A.P histone) This gene encodes a protein shown to interact with huntingtin, which contains an expanded polyglutamine tract in individuals with Huntington's disease (PMID: 9700202). [provided by RefSeq, Aug 2011]

SYTL5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07553002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
H2AP	NM_012274.2	c.272A>G	p.Asn91Ser	missense_variant	1/1	ENST00000341016.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
H2AP	ENST00000341016.5	c.272A>G	p.Asn91Ser	missense_variant	1/1		NM_012274.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.272A>G (p.N91S) alteration is located in exon 1 (coding exon 1) of the HYPM gene. This alteration results from a A to G substitution at nucleotide position 272, causing the asparagine (N) at amino acid position 91 to be replaced by a serine (S). 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	0.096
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.8
DANN	Benign	0.90
DEOGEN2	Benign	0.052	T
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.043
Sift	Benign	0.61	T
Sift4G	Benign	0.59	T
Polyphen		0.71	P
Vest4		0.099
MutPred		0.21		Gain of phosphorylation at N91 (P = 0.0064);
MVP		0.63
MPC		0.012
ClinPred		0.14	T
GERP RS		-0.26
Varity_R		0.044
gMVP		0.026

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-37850364;