1-1354494-C-A

Variant names:

• chr1-1354494-C-A
• rs61730211
• NM_032348.4:c.965G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032348.4(MXRA8):​c.965G>T​(p.Arg322Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,612,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R322C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: MXRA8 NM_032348.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• Publications: 7 publications found

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]

ENSG00000304860 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070369124).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032348.4. 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
	MXRA8	NM_032348.4	MANE Select	c.965G>T	p.Arg322Leu	missense	Exon 6 of 10	NP_115724.1	Q9BRK3-1
	MXRA8	NM_001282585.1		c.965G>T	p.Arg322Leu	missense	Exon 6 of 10	NP_001269514.1	Q9BRK3-2
	MXRA8	NM_001282582.2		c.965G>T	p.Arg322Leu	missense	Exon 7 of 11	NP_001269511.1	Q9BRK3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MXRA8	ENST00000309212.11	TSL:1 MANE Select	c.965G>T	p.Arg322Leu	missense	Exon 6 of 10	ENSP00000307887.6	Q9BRK3-1
	MXRA8	ENST00000342753.8	TSL:1	c.662G>T	p.Arg221Leu	missense	Exon 5 of 9	ENSP00000344998.4	Q9BRK3-4
	MXRA8	ENST00000953650.1		c.1049G>T	p.Arg350Leu	missense	Exon 6 of 10	ENSP00000623709.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000866 AC: 21 AN: 242516 AF XY: 0.0000832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00205

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1459824 Hom.: 0 Cov.: 78 AF XY: 0.0000386 AC XY: 28 AN XY: 726176

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111752

Other (OTH) AF: 0.000199 AC: 12 AN: 60340

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000500 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.14
Sift	Uncertain	0.017	D
Sift4G	Benign	0.097	T
Polyphen		0.39	B
Vest4		0.52
MVP		0.30
MPC		0.25
ClinPred		0.25	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.70
Mutation Taster		=61/39	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: rs61730211; hg19: chr1-1289874;