1-1354494-C-T

Variant names:

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

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>A​(p.Arg322His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. R322C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MXRA8 NM_032348.4 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.25099745).

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>A	p.Arg322His	missense	Exon 6 of 10	NP_115724.1	Q9BRK3-1
	MXRA8	NM_001282585.1		c.965G>A	p.Arg322His	missense	Exon 6 of 10	NP_001269514.1	Q9BRK3-2
	MXRA8	NM_001282582.2		c.965G>A	p.Arg322His	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>A	p.Arg322His	missense	Exon 6 of 10	ENSP00000307887.6	Q9BRK3-1
	MXRA8	ENST00000342753.8	TSL:1	c.662G>A	p.Arg221His	missense	Exon 5 of 9	ENSP00000344998.4	Q9BRK3-4
	MXRA8	ENST00000953650.1		c.1049G>A	p.Arg350His	missense	Exon 6 of 10	ENSP00000623709.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 242516 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459824 Hom.: 0 Cov.: 78 AF XY: 0.00000551 AC XY: 4 AN XY: 726176

African (AFR) AF: 0.00 AC: 0 AN: 33460

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 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: 0.00000810 AC: 9 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000834 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.030
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Benign	0.074	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.22
MutPred		0.34		Gain of glycosylation at T319 (P = 0.1173)
MVP		0.48
MPC		0.47
ClinPred		0.84	D
GERP RS		3.1
Varity_R		0.057
gMVP		0.56
Mutation Taster		=70/30	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; COSMIC: COSV58509960; COSMIC: COSV58509960;