X-110264547-T-C

Position:

• chrX-110264547-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_015365.3(AMMECR1):​c.526A>G​(p.Ile176Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,095,428 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: AMMECR1 NM_015365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMMECR1	NM_015365.3	c.526A>G	p.Ile176Val	missense_variant	2/6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001171689.2	c.157A>G	p.Ile53Val	missense_variant	4/8		NP_001165160.1
AMMECR1	NM_001025580.2	c.474-47915A>G		intron_variant			NP_001020751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMMECR1	ENST00000262844.10	c.526A>G	p.Ile176Val	missense_variant	2/6	1	NM_015365.3	ENSP00000262844.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1095428 Hom.: 0 Cov.: 28 AF XY: 0.00000831 AC XY: 3 AN XY: 361134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000714

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.88	N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.98	D;.
Vest4		0.64
MutPred		0.86		Gain of MoRF binding (P = 0.1161);.;
MVP		0.79
MPC		1.5
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs2067757957; hg19: chrX-109507775;