X-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: Labcorp Genetics (formerly Invitae), Illumina
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015365.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMMECR1	NM_015365.3	MANE Select	c.841A>C	p.Lys281Gln	missense	Exon 5 of 6	NP_056180.1	Q9Y4X0-1
	AMMECR1	NM_001025580.2		c.730A>C	p.Lys244Gln	missense	Exon 4 of 5	NP_001020751.1	Q9Y4X0-3
	AMMECR1	NM_001171689.2		c.472A>C	p.Lys158Gln	missense	Exon 7 of 8	NP_001165160.1	Q9Y4X0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMMECR1	ENST00000262844.10	TSL:1 MANE Select	c.841A>C	p.Lys281Gln	missense	Exon 5 of 6	ENSP00000262844.5	Q9Y4X0-1
	AMMECR1	ENST00000372059.6	TSL:1	c.730A>C	p.Lys244Gln	missense	Exon 4 of 5	ENSP00000361129.2	Q9Y4X0-3
	AMMECR1	ENST00000686065.1		c.841A>C	p.Lys281Gln	missense	Exon 5 of 7	ENSP00000509935.1	A0A8I5KSJ4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.022	D
Sift4G	Benign	0.096	T
Polyphen		0.60	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;