X-110201006-C-A

Variant names:

• chrX-110201006-C-A
• NM_015365.3:c.835G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_015365.3(AMMECR1):​c.835G>T​(p.Gly279*) 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 U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 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 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 rank	MANE	Protein	UniProt
AMMECR1	NM_015365.3	c.835G>T	p.Gly279*	stop_gained	Exon 5 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2	c.724G>T	p.Gly242*	stop_gained	Exon 4 of 5		NP_001020751.1
AMMECR1	NM_001171689.2	c.466G>T	p.Gly156*	stop_gained	Exon 7 of 8		NP_001165160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10	c.835G>T	p.Gly279*	stop_gained	Exon 5 of 6	1	NM_015365.3	ENSP00000262844.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

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

Mar 17, 2025

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 strong, PM2 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	37
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
Vest4		0.48
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=9/191	disease causing

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

Other links and lift over

hg19: chrX-109444234;