X-110216604-T-A

Variant names:

• chrX-110216604-T-A
• rs201052711
• NM_015365.3:c.613A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015365.3(AMMECR1):​c.613A>T​(p.Met205Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000915 in 1,093,004 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M205V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AMMECR1 NM_015365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31350744).

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.613A>T	p.Met205Leu	missense	Exon 3 of 6	NP_056180.1	Q9Y4X0-1
	AMMECR1	NM_001025580.2		c.502A>T	p.Met168Leu	missense	Exon 2 of 5	NP_001020751.1	Q9Y4X0-3
	AMMECR1	NM_001171689.2		c.244A>T	p.Met82Leu	missense	Exon 5 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.613A>T	p.Met205Leu	missense	Exon 3 of 6	ENSP00000262844.5	Q9Y4X0-1
	AMMECR1	ENST00000372059.6	TSL:1	c.502A>T	p.Met168Leu	missense	Exon 2 of 5	ENSP00000361129.2	Q9Y4X0-3
	AMMECR1	ENST00000686065.1		c.613A>T	p.Met205Leu	missense	Exon 3 of 7	ENSP00000509935.1	A0A8I5KSJ4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093004 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 358666

African (AFR) AF: 0.00 AC: 0 AN: 26251

American (AMR) AF: 0.00 AC: 0 AN: 35040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19284

East Asian (EAS) AF: 0.00 AC: 0 AN: 30098

South Asian (SAS) AF: 0.00 AC: 0 AN: 53642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40477

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838214

Other (OTH) AF: 0.0000218 AC: 1 AN: 45882

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		6.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.26	N
REVEL	Benign	0.19
Sift	Benign	0.45	T
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.54
MutPred		0.57		Loss of disorder (P = 0.1516)
MVP		0.92
MPC		0.66
ClinPred		0.84	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.53
gMVP		0.85
Mutation Taster		=82/18	polymorphism

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

dbSNP: rs201052711; hg19: chrX-109459832;