rs146457392

Variant names:

• chrX-110201019-T-C
• rs146457392
• NM_015365.3:c.822A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.23
• 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: Illumina, Labcorp Genetics (formerly Invitae)
• Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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	UniProt
AMMECR1	NM_015365.3	c.822A>G	p.Leu274Leu	synonymous_variant	Exon 5 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2	c.711A>G	p.Leu237Leu	synonymous_variant	Exon 4 of 5		NP_001020751.1
AMMECR1	NM_001171689.2	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	c.822A>G	p.Leu274Leu	synonymous_variant	Exon 5 of 6	1	NM_015365.3	ENSP00000262844.5

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 111887 Hom.: 0 Cov.: 23

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: 31 AN: 182238 AF XY: 0.000164

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.: 1 Cov.: 27 AF XY: 0.000118 AC XY: 42 AN XY: 357008

African (AFR) AF: 0.00 AC: 0 AN: 26211

American (AMR) AF: 0.00 AC: 0 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19275

East Asian (EAS) AF: 0.00 AC: 0 AN: 30154

South Asian (SAS) AF: 0.00 AC: 0 AN: 53946

European-Finnish (FIN) AF: 0.000922 AC: 37 AN: 40142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.000138 AC: 115 AN: 835851

Other (OTH) AF: 0.000153 AC: 7 AN: 45828

GnomAD4 genome AF: 0.000107 AC: 12 AN: 111887 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34097

African (AFR) AF: 0.0000325 AC: 1 AN: 30767

American (AMR) AF: 0.0000946 AC: 1 AN: 10575

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2667

European-Finnish (FIN) AF: 0.000655 AC: 4 AN: 6106

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

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53110

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.000285 Hom.: 1

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

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.1
DANN	Benign	0.81
PhyloP100		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs146457392; hg19: chrX-109444247;