Genetic Variant NM_015365.3:c.613A>T (chrX-110216604-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

Publications

0 publications found

Variant links:

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

AMMECR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1093004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26251

American (AMR)

AF:

0.00

AC:

AN:

35040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19284

East Asian (EAS)

AF:

0.00

AC:

AN:

30098

South Asian (SAS)

AF:

0.00

AC:

AN:

53642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40477

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838214

Other (OTH)

AF:

0.0000218

AC:

AN:

45882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.19

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.64

M_CAP

Benign

0.054

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

6.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.26

REVEL

Benign

0.19

Sift

Benign

0.45

Sift4G

Benign

0.18

Polyphen

0.0020

Vest4

0.54

MutPred

0.57

Loss of disorder (P = 0.1516)

MVP

0.92

MPC

0.66

ClinPred

0.84

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

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over