Genetic Variant AMMECR1:p.Ala311Thr (chrX-110198591-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015365.3(AMMECR1):c.931G>A(p.Ala311Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000313 in 1,201,291 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 133 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00032 ( 0 hom. 123 hem. )

Consequence

AMMECR1
NM_015365.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.70

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.072279245).

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AMMECR1	NM_015365.3 link	c.931G>A	p.Ala311Thr	missense_variant	Exon 6 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2 link	c.820G>A	p.Ala274Thr	missense_variant	Exon 5 of 5		NP_001020751.1
AMMECR1	NM_001171689.2 link	c.562G>A	p.Ala188Thr	missense_variant	Exon 8 of 8		NP_001165160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10 link	c.931G>A	p.Ala311Thr	missense_variant	Exon 6 of 6	1	NM_015365.3	ENSP00000262844.5		Q9Y4X0-1

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

111571

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

33801

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000663

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:

0.000283

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000133

AC:

AN:

172346

Hom.:

AF XY:

0.000121

AC XY:

AN XY:

57948

show subpopulations

Gnomad AFR exome

AF:

0.0000801

Gnomad AMR exome

AF:

0.0000390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000245

Gnomad OTH exome

AF:

0.000476

GnomAD4 exome

AF:

0.000323

AC:

352

AN:

1089668

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

123

AN XY:

356124

show subpopulations

Gnomad4 AFR exome

AF:

0.0000386

Gnomad4 AMR exome

AF:

0.000117

Gnomad4 ASJ exome

AF:

0.0000526

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000397

Gnomad4 OTH exome

AF:

0.000263

GnomAD4 genome

AF:

0.000215

AC:

AN:

111623

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

33863

show subpopulations

Gnomad4 AFR

AF:

0.0000651

Gnomad4 AMR

AF:

0.000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000283

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000349

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.931G>A (p.A311T) alteration is located in exon 6 (coding exon 6) of the AMMECR1 gene. This alteration results from a G to A substitution at nucleotide position 931, causing the alanine (A) at amino acid position 311 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.14

B;P;.

Vest4

0.39

MVP

0.35

MPC

0.72

ClinPred

0.033

GERP RS

6.0

Varity_R

0.40

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over