NM_015365.3:c.965T>C

Variant names:

• chrX-110198557-A-G
• rs372054643
• NM_015365.3:c.965T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015365.3(AMMECR1):​c.965T>C​(p.Ile322Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I322M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 7 hem.)
  • Failed GnomAD Quality Control
• Consequence: AMMECR1 NM_015365.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32306755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMMECR1	NM_015365.3	c.965T>C	p.Ile322Thr	missense_variant	Exon 6 of 6	ENST00000262844.10	NP_056180.1
AMMECR1	NM_001025580.2	c.854T>C	p.Ile285Thr	missense_variant	Exon 5 of 5		NP_001020751.1
AMMECR1	NM_001171689.2	c.596T>C	p.Ile199Thr	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.965T>C	p.Ile322Thr	missense_variant	Exon 6 of 6	1	NM_015365.3	ENSP00000262844.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000417 AC: 7 AN: 167990 AF XY: 0.0000925

Gnomad AFR exome AF: 0.0000794

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000662

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000119 AC: 13 AN: 1087993 Hom.: 0 Cov.: 28 AF XY: 0.0000197 AC XY: 7 AN XY: 355069

African (AFR) AF: 0.0000385 AC: 1 AN: 25997

American (AMR) AF: 0.00 AC: 0 AN: 34258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18827

East Asian (EAS) AF: 0.00 AC: 0 AN: 29928

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40197

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4071

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 836695

Other (OTH) AF: 0.00 AC: 0 AN: 45632

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.965T>C (p.I322T) alteration is located in exon 6 (coding exon 6) of the AMMECR1 gene. This alteration results from a T to C substitution at nucleotide position 965, causing the isoleucine (I) at amino acid position 322 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	0.24
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	21
DANN	Benign	0.55
DEOGEN2	Benign	0.14	T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N;.;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.39	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.69
MVP		0.92
MPC		0.89
ClinPred		0.14	T
GERP RS		6.0
Varity_R		0.27
gMVP		0.78
Mutation Taster		=92/8	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: rs372054643; hg19: chrX-109441785;