rs35718712

Variant names:

• chrX-64192455-C-A
• rs35718712
• NM_152424.4:c.832G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-64192455-C-A
• chrX-64192455-C-G
• chrX-64192455-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152424.4(AMER1):​c.832G>T​(p.Ala278Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,204,351 control chromosomes in the GnomAD database, including 6 homozygotes. There are 205 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A278V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., 112 hem., cov: 24)
  • Exomes 𝑓: 0.00035 (3 hom. 93 hem.)
• Consequence: AMER1 NM_152424.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.372
• Publications: 4 publications found

Genes affected

AMER1 (HGNC:26837): (APC membrane recruitment protein 1) The protein encoded by this gene upregulates trancriptional activation by the Wilms tumor protein and interacts with many other proteins, including CTNNB1, APC, AXIN1, and AXIN2. Defects in this gene are a cause of osteopathia striata with cranial sclerosis (OSCS). [provided by RefSeq, May 2010]

AMER1 Gene-Disease associations (from GenCC):

• osteopathia striata with cranial sclerosis

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037240684).
• BP6: Variant X-64192455-C-A is Benign according to our data. Variant chrX-64192455-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMER1	NM_152424.4	MANE Select	c.832G>T	p.Ala278Ser	missense	Exon 2 of 2	NP_689637.3	Q5JTC6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMER1	ENST00000374869.8	TSL:5 MANE Select	c.832G>T	p.Ala278Ser	missense	Exon 2 of 2	ENSP00000364003.4	Q5JTC6-1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 384 AN: 113307 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000924

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: 0.00

Gnomad OTH AF: 0.00130

GnomAD2 exomes AF: 0.00114 AC: 196 AN: 171700 AF XY: 0.000880

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000800

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000258

Gnomad OTH exome AF: 0.000474

GnomAD4 exome AF: 0.000346 AC: 378 AN: 1090992 Hom.: 3 Cov.: 34 AF XY: 0.000260 AC XY: 93 AN XY: 357684

African (AFR) AF: 0.0120 AC: 314 AN: 26130

American (AMR) AF: 0.000841 AC: 29 AN: 34490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18766

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.0000382 AC: 2 AN: 52348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40075

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4080

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 839152

Other (OTH) AF: 0.000634 AC: 29 AN: 45771

GnomAD4 genome AF: 0.00340 AC: 385 AN: 113359 Hom.: 3 Cov.: 24 AF XY: 0.00315 AC XY: 112 AN XY: 35507

African (AFR) AF: 0.0119 AC: 373 AN: 31268

American (AMR) AF: 0.000923 AC: 10 AN: 10840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2662

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6336

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53430

Other (OTH) AF: 0.00129 AC: 2 AN: 1555

Alfa AF: 0.000931 Hom.: 40

Bravo AF: 0.00409

ESP6500AA AF: 0.0117 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00124 AC: 151

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.25
DANN	Benign	0.64
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.37
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.023
Sift	Benign	0.33	T
Sift4G	Benign	0.75	T
Polyphen		0.0060	B
Vest4		0.11
MVP		0.27
MPC		0.026
ClinPred		0.011	T
GERP RS		2.1
Varity_R		0.047
gMVP		0.073
Mutation Taster		=100/0	polymorphism (auto)

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: rs35718712; hg19: chrX-63412335;