X-110201050-C-A

Variant summary

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

The NM_015365.3(AMMECR1):c.791G>T(p.Gly264Val) variant causes a missense, splice region 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. 13/21 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMMECR1 NM_015365.3 missense, splice_region
• Scores: Splicing: ADA: 0.9965
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMMECR1	NM_015365.3	c.791G>T	p.Gly264Val	missense_variant, splice_region_variant	5/6	ENST00000262844.10
AMMECR1	NM_001025580.2	c.680G>T	p.Gly227Val	missense_variant, splice_region_variant	4/5
AMMECR1	NM_001171689.2	c.422G>T	p.Gly141Val	missense_variant, splice_region_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMMECR1	ENST00000262844.10	c.791G>T	p.Gly264Val	missense_variant, splice_region_variant	5/6	1	NM_015365.3	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 21

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

Mar 24, 2021

This sequence change is predicted to replace Glycine with Valine at codon 264 of the AMMECR1 protein (p.(Gly264Val)). The Glycine residue is very highly conserved (100 vertebrates, UCSC), and is not in any annotated domain. There is a large physicochemical difference between Glycine and Valine. 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). 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	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.6	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.69		Loss of disorder (P = 0.0825);.;.;
MVP		0.95
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.030		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-109444278;