4-89909310-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007351.3. 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
	MMRN1	NM_007351.3	MANE Select	c.658C>T	p.Pro220Ser	missense	Exon 2 of 8	NP_031377.2
	MMRN1	NM_001371403.1		c.658C>T	p.Pro220Ser	missense	Exon 3 of 9	NP_001358332.1	Q13201-1
	MMRN1	NM_001410735.1		c.-117C>T		5_prime_UTR	Exon 2 of 8	NP_001397664.1	E7EPG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMRN1	ENST00000264790.7	TSL:1 MANE Select	c.658C>T	p.Pro220Ser	missense	Exon 2 of 8	ENSP00000264790.2	Q13201-1
	MMRN1	ENST00000394980.5	TSL:5	c.658C>T	p.Pro220Ser	missense	Exon 3 of 9	ENSP00000378431.1	Q13201-1
	MMRN1	ENST00000955234.1		c.658C>T	p.Pro220Ser	missense	Exon 2 of 8	ENSP00000625293.1

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

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

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109670

Other (OTH) AF: 0.00 AC: 0 AN: 60154

⚠️ 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 Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.28
Sift	Benign	0.48	T
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.61		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
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs904683690; hg19: chr4-90830461;