X-110201042-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015365.3(AMMECR1):c.799C>T(p.His267Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMMECR1 NM_015365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

AMMECR1 (HGNC:467): (AMMECR nuclear protein 1) The exact function of this gene is not known, however, submicroscopic deletion of the X chromosome including this gene, COL4A5, and FACL4 genes, result in a contiguous gene deletion syndrome, the AMME complex (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMMECR1	NM_015365.3	c.799C>T	p.His267Tyr	missense_variant	5/6	ENST00000262844.10
AMMECR1	NM_001025580.2	c.688C>T	p.His230Tyr	missense_variant	4/5
AMMECR1	NM_001171689.2	c.430C>T	p.His144Tyr	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMMECR1	ENST00000262844.10	c.799C>T	p.His267Tyr	missense_variant	5/6	1	NM_015365.3	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Nov 20, 2020

This sequence change is predicted to replace Histidine with Tyrosine at codon 267 of the AMMECR1 protein (p.(His267Tyr)). The Histidine residue is very highly conserved (100 vertebrates, UCSC), and is not in any annotated domain. There is a moderate physicochemical difference between Histidine and Tyrosine. The variant is absent from a large population cohort (PM2, gnomAD v2.1.1 and v3). This variant has not been previously reported. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3, 5/5 algorithms). A variant at same residue (p.(His267Arg)) is present in gnomAD with a frequency of one heterozygote (gnomAD v2.1.1), and has not been otherwise reported. Based on the classification guideline RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. The following criteria are met: PM2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D;N;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.76
MutPred		0.50		Gain of phosphorylation at H267 (P = 0.0668);.;.;
MVP		0.68
MPC		1.7
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.90

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: chrX-109444270;