X-3310390-C-T

Variant names:

• chrX-3310390-C-T
• rs148941538
• NM_015419.4:c.7813G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015419.4(MXRA5):​c.7813G>A​(p.Gly2605Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,203,052 control chromosomes in the GnomAD database, including 23 homozygotes. There are 442 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (10 hom., 196 hem., cov: 19)
  • Exomes 𝑓: 0.00085 (13 hom. 246 hem.)
• Consequence: MXRA5 NM_015419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200
• Publications: 1 publications found

Genes affected

MXRA5 (HGNC:7539): (matrix remodeling associated 5) This gene encodes one of the matrix-remodelling associated proteins. This protein contains 7 leucine-rich repeats and 12 immunoglobulin-like C2-type domains related to perlecan. This gene has a pseudogene on chromosome Y. [provided by RefSeq, Mar 2010]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011803716).
• BP6: Variant X-3310390-C-T is Benign according to our data. Variant chrX-3310390-C-T is described in ClinVar as Benign. ClinVar VariationId is 777781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0086 (932/108314) while in subpopulation AFR AF = 0.0286 (855/29877). AF 95% confidence interval is 0.027. There are 10 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015419.4. 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
	MXRA5	NM_015419.4	MANE Select	c.7813G>A	p.Gly2605Ser	missense	Exon 7 of 7	NP_056234.2	Q9NR99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MXRA5	ENST00000217939.7	TSL:5 MANE Select	c.7813G>A	p.Gly2605Ser	missense	Exon 7 of 7	ENSP00000217939.5	Q9NR99

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 932 AN: 108270 Hom.: 10 Cov.: 19

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00451

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: 0.000135

Gnomad OTH AF: 0.00762

GnomAD2 exomes AF: 0.00196 AC: 334 AN: 170317 AF XY: 0.000991

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000670

Gnomad OTH exome AF: 0.000715

GnomAD4 exome AF: 0.000847 AC: 927 AN: 1094738 Hom.: 13 Cov.: 35 AF XY: 0.000682 AC XY: 246 AN XY: 360482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0267 AC: 700 AN: 26239

American (AMR) AF: 0.00208 AC: 73 AN: 35022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19342

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30162

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40202

Middle Eastern (MID) AF: 0.000251 AC: 1 AN: 3988

European-Non Finnish (NFE) AF: 0.0000762 AC: 64 AN: 840036

Other (OTH) AF: 0.00190 AC: 87 AN: 45901

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00860 AC: 932 AN: 108314 Hom.: 10 Cov.: 19 AF XY: 0.00640 AC XY: 196 AN XY: 30624

African (AFR) AF: 0.0286 AC: 855 AN: 29877

American (AMR) AF: 0.00451 AC: 46 AN: 10205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2598

East Asian (EAS) AF: 0.00 AC: 0 AN: 3389

South Asian (SAS) AF: 0.00 AC: 0 AN: 2324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5603

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000135 AC: 7 AN: 51981

Other (OTH) AF: 0.00751 AC: 11 AN: 1464

Alfa AF: 0.00322 Hom.: 22

ESP6500AA AF: 0.0225 AC: 85

ESP6500EA AF: 0.000151 AC: 1

ExAC AF: 0.00210 AC: 254

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.052
DANN	Benign	0.39
DEOGEN2	Benign	0.0010	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	-0.96	N
PhyloP100		0.020
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.24
Sift	Benign	0.74	T
Sift4G	Benign	0.88	T
Polyphen		0.082	B
Vest4		0.056
MVP		0.47
MPC		0.066
ClinPred		0.0025	T
GERP RS		-0.32
Varity_R		0.051
gMVP		0.29
Mutation Taster		=99/1	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: rs148941538; hg19: chrX-3228431; COSMIC: COSV99028394;