X-110198591-C-T

Variant names:

• chrX-110198591-C-T
• rs145206893
• NM_015365.3:c.931G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70
• Publications: 1 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: Likely_benign. The variant received -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	UniProt
AMMECR1	NM_015365.3	c.931G>A	p.Ala311Thr	missense_variant	Exon 6 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2	c.820G>A	p.Ala274Thr	missense_variant	Exon 5 of 5		NP_001020751.1
AMMECR1	NM_001171689.2	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	c.931G>A	p.Ala311Thr	missense_variant	Exon 6 of 6	1	NM_015365.3	ENSP00000262844.5

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 24 AN: 111571 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000133 AC: 23 AN: 172346 AF XY: 0.000121

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 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.: 0 Cov.: 28 AF XY: 0.000345 AC XY: 123 AN XY: 356124

African (AFR) AF: 0.0000386 AC: 1 AN: 25915

American (AMR) AF: 0.000117 AC: 4 AN: 34099

Ashkenazi Jewish (ASJ) AF: 0.0000526 AC: 1 AN: 19006

East Asian (EAS) AF: 0.00 AC: 0 AN: 29843

South Asian (SAS) AF: 0.00 AC: 0 AN: 52667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40360

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4089

European-Non Finnish (NFE) AF: 0.000397 AC: 333 AN: 837980

Other (OTH) AF: 0.000263 AC: 12 AN: 45709

GnomAD4 genome AF: 0.000215 AC: 24 AN: 111623 Hom.: 0 Cov.: 23 AF XY: 0.000295 AC XY: 10 AN XY: 33863

African (AFR) AF: 0.0000651 AC: 2 AN: 30702

American (AMR) AF: 0.000662 AC: 7 AN: 10567

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2645

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6025

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000283 AC: 15 AN: 53067

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.000334 Hom.: 20

Bravo AF: 0.000306

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;.;.
PhyloP100		5.7
PrimateAI	Pathogenic	0.82	D
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	T
GERP RS		6.0
Varity_R		0.40
gMVP		0.71
Mutation Taster		=94/6	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: rs145206893; hg19: chrX-109441819; COSMIC: COSV99035350;