rs1057519338

Positions:

• chrX-110264571-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_015365.3(AMMECR1):​c.502C>T​(p.Arg168Ter) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMMECR1 NM_015365.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.68

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMMECR1	NM_015365.3	c.502C>T	p.Arg168Ter	stop_gained	2/6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001171689.2	c.133C>T	p.Arg45Ter	stop_gained	4/8		NP_001165160.1
AMMECR1	NM_001025580.2	c.474-47939C>T		intron_variant			NP_001020751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10	c.502C>T	p.Arg168Ter	stop_gained	2/6	1	NM_015365.3	ENSP00000262844	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 25, 2018	- -
Pathogenic, no assertion criteria provided	research	Genetics Division, Universidade Federal de Sao Paulo	-	The patient with this variant has AMMECR1 loss of function and overlapping phenotypes with the patients described in Basel-Vanagaite et al. 2017 (PMID: 28089922) and Andreoletti et al. 2017 (PMID: 27811305). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 02, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant is associated with skipping of exon 2 but is expected to preserve the integrity of the reading frame (PMID: 28089922). This variant has been observed in individual(s) with clinical features of AMMECR1-related conditions (PMID: 29193635, 28089922). This variant is also known as p.Arg45*. ClinVar contains an entry for this variant (Variation ID: 375305). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg168*) in the AMMECR1 gene. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.59
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519338; hg19: chrX-109507799;