Genetic Variant NM_015365.3:c.822A>G (chrX-110201019-T-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_015365.3(AMMECR1):c.822A>G(p.Leu274Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,202,537 control chromosomes in the GnomAD database, including 1 homozygotes. There are 46 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00015 ( 1 hom. 42 hem. )

Consequence

AMMECR1
NM_015365.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.23

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: Illumina, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant X-110201019-T-C is Benign according to our data. Variant chrX-110201019-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 721778.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=3.23 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AMMECR1	NM_015365.3 link	c.822A>G	p.Leu274Leu	synonymous_variant	Exon 5 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2 link	c.711A>G	p.Leu237Leu	synonymous_variant	Exon 4 of 5		NP_001020751.1
AMMECR1	NM_001171689.2 link	c.453A>G	p.Leu151Leu	synonymous_variant	Exon 7 of 8		NP_001165160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10 link	c.822A>G	p.Leu274Leu	synonymous_variant	Exon 5 of 6	1	NM_015365.3	ENSP00000262844.5		Q9Y4X0-1

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

111887

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000946

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000655

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000170

AC:

AN:

182238

AF XY:

0.000164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000961

Gnomad NFE exome

AF:

0.000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000146

AC:

159

AN:

1090650

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

357008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26211

American (AMR)

AF:

0.00

AC:

AN:

35142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19275

East Asian (EAS)

AF:

0.00

AC:

AN:

30154

South Asian (SAS)

AF:

0.00

AC:

AN:

53946

European-Finnish (FIN)

AF:

0.000922

AC:

AN:

40142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4101

European-Non Finnish (NFE)

AF:

0.000138

AC:

115

AN:

835851

Other (OTH)

AF:

0.000153

AC:

AN:

45828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000107

AC:

AN:

111887

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34097

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30767

American (AMR)

AF:

0.0000946

AC:

AN:

10575

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.000655

AC:

AN:

6106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53110

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000756

EpiCase

AF:

0.0000548

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.1

(source)

DANN

Benign

0.81

PhyloP100

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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NM_015365.3:c.822A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over