X-110200980-T-A

Variant names:

• chrX-110200980-T-A
• rs1160009207
• NM_015365.3:c.861A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015365.3(AMMECR1):​c.861A>T​(p.Glu287Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,290 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E287E) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: AMMECR1 NM_015365.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11808616).

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.861A>T	p.Glu287Asp	missense	Exon 5 of 6	NP_056180.1	Q9Y4X0-1
	AMMECR1	NM_001025580.2		c.750A>T	p.Glu250Asp	missense	Exon 4 of 5	NP_001020751.1	Q9Y4X0-3
	AMMECR1	NM_001171689.2		c.492A>T	p.Glu164Asp	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.861A>T	p.Glu287Asp	missense	Exon 5 of 6	ENSP00000262844.5	Q9Y4X0-1
	AMMECR1	ENST00000372059.6	TSL:1	c.750A>T	p.Glu250Asp	missense	Exon 4 of 5	ENSP00000361129.2	Q9Y4X0-3
	AMMECR1	ENST00000686065.1		c.861A>T	p.Glu287Asp	missense	Exon 5 of 7	ENSP00000509935.1	A0A8I5KSJ4

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112290 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112290 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34474

African (AFR) AF: 0.00 AC: 0 AN: 30943

American (AMR) AF: 0.00 AC: 0 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6173

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53206

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.000132 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.13	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.069
Sift	Benign	0.64	T
Sift4G	Benign	0.66	T
Polyphen		0.024	B
Vest4		0.14
MutPred		0.56		Gain of helix (P = 0.132)
MVP		0.15
MPC		0.64
ClinPred		0.37	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.71
Mutation Taster		=97/3	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

dbSNP: rs1160009207; hg19: chrX-109444208;