chrX-110201000-T-G

Variant names:

• chrX-110201000-T-G
• NM_015365.3:c.841A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015365.3(AMMECR1):​c.841A>C​(p.Lys281Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.67
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.841A>C	p.Lys281Gln	missense_variant	Exon 5 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2	c.730A>C	p.Lys244Gln	missense_variant	Exon 4 of 5		NP_001020751.1
AMMECR1	NM_001171689.2	c.472A>C	p.Lys158Gln	missense_variant	Exon 7 of 8		NP_001165160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10	c.841A>C	p.Lys281Gln	missense_variant	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

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841A>C (p.K281Q) alteration is located in exon 5 (coding exon 5) of the AMMECR1 gene. This alteration results from a A to C substitution at nucleotide position 841, causing the lysine (K) at amino acid position 281 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	L;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.022	D;D;T
Sift4G	Benign	0.096	T;T;T
Polyphen		0.60	P;P;.
Vest4		0.75
MutPred		0.40		Loss of methylation at K281 (P = 0.0116);.;.;
MVP		0.49
MPC		1.7
ClinPred		0.97	D
GERP RS		6.1
Varity_R		0.78
gMVP		0.84
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

hg19: chrX-109444228;