rs1057519338

Variant names:

• chrX-110264571-G-A
• rs1057519338
• NM_015365.3:c.502C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015365.3(AMMECR1):​c.502C>T​(p.Arg168*) 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AMMECR1 NM_015365.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.68
• Publications: 1 publications found

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]

AMMECR1 Gene-Disease associations (from GenCC):

• midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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
• PP5: Variant X-110264571-G-A is Pathogenic according to our data. Variant chrX-110264571-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375305.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMMECR1	NM_015365.3	c.502C>T	p.Arg168*	stop_gained	Exon 2 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001171689.2	c.133C>T	p.Arg45*	stop_gained	Exon 4 of 8		NP_001165160.1
AMMECR1	NM_001025580.2	c.474-47939C>T		intron_variant	Intron 1 of 4		NP_001020751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10	c.502C>T	p.Arg168*	stop_gained	Exon 2 of 6	1	NM_015365.3	ENSP00000262844.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis Pathogenic:3

-

Genetics Division, Universidade Federal de Sao Paulo

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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). -

Jan 25, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3_supporting, PM2 -

not provided Uncertain:1

Apr 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		7.7
Vest4		0.59
GERP RS		5.4
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057519338; hg19: chrX-109507799;