Genetic Variant MMRN1:p.Pro220Thr (chr4-89909310-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_007351.3(MMRN1):c.658C>A(p.Pro220Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,609,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MMRN1
NM_007351.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

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]

MMRN1 links:

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ACMG classification

Classification made for transcript

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, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMRN1	NM_007351.3 link	c.658C>A	p.Pro220Thr	missense_variant	Exon 2 of 8	ENST00000264790.7	NP_031377.2	Q13201-1
MMRN1	NM_001371403.1 link	c.658C>A	p.Pro220Thr	missense_variant	Exon 3 of 9		NP_001358332.1
MMRN1	XM_047449831.1 link	c.658C>A	p.Pro220Thr	missense_variant	Exon 3 of 8		XP_047305787.1
MMRN1	NM_001410735.1 link	c.-117C>A		5_prime_UTR_variant	Exon 2 of 8		NP_001397664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMRN1	ENST00000264790.7 link	c.658C>A	p.Pro220Thr	missense_variant	Exon 2 of 8	1	NM_007351.3	ENSP00000264790.2	Q13201-1
MMRN1	ENST00000394980.5 link	c.658C>A	p.Pro220Thr	missense_variant	Exon 3 of 9	5		ENSP00000378431.1	Q13201-1
MMRN1	ENST00000508372 link	c.-117C>A		5_prime_UTR_variant	Exon 2 of 8	2		ENSP00000426461.1	E7EPG1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151378

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

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

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458302

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000898

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151378

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73892

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000660

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.658C>A (p.P220T) alteration is located in exon 2 (coding exon 2) of the MMRN1 gene. This alteration results from a C to A substitution at nucleotide position 658, causing the proline (P) at amino acid position 220 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.71

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

1.2

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.36

T;T

Sift4G

Benign

0.16

T;T

Polyphen

1.0

D;D

Vest4

0.79

MutPred

0.64

Gain of catalytic residue at P220 (P = 0.0134);Gain of catalytic residue at P220 (P = 0.0134);

MVP

0.58

MPC

0.087

ClinPred

0.52

GERP RS

5.3

Varity_R

0.14

gMVP

0.31

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over