4-89909310-C-T

Variant names:

• chr4-89909310-C-T
• rs904683690
• NM_007351.3:c.658C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007351.3(MMRN1):​c.658C>T​(p.Pro220Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P220T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MMRN1 NM_007351.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.47

Genes affected

MMRN1 (HGNC:7178): (multimerin 1) Multimerin is a massive, soluble protein found in platelets and in the endothelium of blood vessels. It is comprised of subunits linked by interchain disulfide bonds to form large, variably sized homomultimers. Multimerin is a factor V/Va-binding protein and may function as a carrier protein for platelet factor V. It may also have functions as an extracellular matrix or adhesive protein. Recently, patients with an unusual autosomal-dominant bleeding disorder (factor V Quebec) were found to have a deficiency of platelet multimerin. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMRN1	NM_007351.3	c.658C>T	p.Pro220Ser	missense_variant	Exon 2 of 8	ENST00000264790.7	NP_031377.2
MMRN1	NM_001371403.1	c.658C>T	p.Pro220Ser	missense_variant	Exon 3 of 9		NP_001358332.1
MMRN1	XM_047449831.1	c.658C>T	p.Pro220Ser	missense_variant	Exon 3 of 8		XP_047305787.1
MMRN1	NM_001410735.1	c.-117C>T		5_prime_UTR_variant	Exon 2 of 8		NP_001397664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMRN1	ENST00000264790.7	c.658C>T	p.Pro220Ser	missense_variant	Exon 2 of 8	1	NM_007351.3	ENSP00000264790.2
MMRN1	ENST00000394980.5	c.658C>T	p.Pro220Ser	missense_variant	Exon 3 of 9	5		ENSP00000378431.1
MMRN1	ENST00000508372	c.-117C>T		5_prime_UTR_variant	Exon 2 of 8	2		ENSP00000426461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458302 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.55	N;N
REVEL	Benign	0.28
Sift	Benign	0.48	T;T
Sift4G	Uncertain	0.043	D;D
Polyphen		1.0	D;D
Vest4		0.72
MutPred		0.61		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.55
MPC		0.086
ClinPred		0.74	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs904683690; hg19: chr4-90830461;