1-1353913-A-G

Position:

• chr1-1353913-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The ENST00000309212.11(MXRA8):​c.1238T>C​(p.Ile413Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000592 in 152,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I413N) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.000059 (0 hom., cov: 33)
• Consequence: MXRA8 ENST00000309212.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.19

Genes affected

MXRA8 (HGNC:7542): (matrix remodeling associated 8) Predicted to be involved in establishment of glial blood-brain barrier. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1353913-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402162.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MXRA8	NM_032348.4	c.1238T>C	p.Ile413Thr	missense_variant	9/10	ENST00000309212.11	NP_115724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MXRA8	ENST00000309212.11	c.1238T>C	p.Ile413Thr	missense_variant	9/10	1	NM_032348.4	ENSP00000307887	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152036 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246698 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133848

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152036 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74258

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000644 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	.;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.95, 0.97	.;P;D;.
Vest4		0.79
MVP		0.55
MPC		0.28
ClinPred		0.81	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374879755; hg19: chr1-1289293;