chr4-89895143-A-G

Variant names:

• chr4-89895143-A-G
• rs1442138
• NM_007351.3:c.172A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007351.3(MMRN1):​c.172A>G​(p.Thr58Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,613,694 control chromosomes in the GnomAD database, including 3,373 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.079 (646 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2727 hom.)
• Consequence: MMRN1 NM_007351.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.739
• Publications: 25 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

ENSG00000301182 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013822615).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMRN1	NM_007351.3	c.172A>G	p.Thr58Ala	missense_variant	Exon 1 of 8	ENST00000264790.7	NP_031377.2
MMRN1	NM_001371403.1	c.172A>G	p.Thr58Ala	missense_variant	Exon 2 of 9		NP_001358332.1
MMRN1	XM_047449831.1	c.172A>G	p.Thr58Ala	missense_variant	Exon 2 of 8		XP_047305787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMRN1	ENST00000264790.7	c.172A>G	p.Thr58Ala	missense_variant	Exon 1 of 8	1	NM_007351.3	ENSP00000264790.2

Frequencies

GnomAD3 genomes AF: 0.0794 AC: 12060 AN: 151934 Hom.: 644 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0573

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0599

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0405

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0567

Gnomad OTH AF: 0.0795

GnomAD2 exomes AF: 0.0526 AC: 13173 AN: 250484 AF XY: 0.0511

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0294

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0465

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0549

GnomAD4 exome AF: 0.0571 AC: 83410 AN: 1461642 Hom.: 2727 Cov.: 35 AF XY: 0.0560 AC XY: 40726 AN XY: 727128

African (AFR) AF: 0.156 AC: 5216 AN: 33466

American (AMR) AF: 0.0327 AC: 1461 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 1438 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39642

South Asian (SAS) AF: 0.0380 AC: 3274 AN: 86256

European-Finnish (FIN) AF: 0.0466 AC: 2486 AN: 53396

Middle Eastern (MID) AF: 0.0695 AC: 401 AN: 5766

European-Non Finnish (NFE) AF: 0.0589 AC: 65492 AN: 1111906

Other (OTH) AF: 0.0602 AC: 3637 AN: 60384

GnomAD4 genome AF: 0.0794 AC: 12076 AN: 152052 Hom.: 646 Cov.: 32 AF XY: 0.0762 AC XY: 5665 AN XY: 74338

African (AFR) AF: 0.154 AC: 6379 AN: 41420

American (AMR) AF: 0.0506 AC: 772 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 208 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4820

European-Finnish (FIN) AF: 0.0405 AC: 429 AN: 10594

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0567 AC: 3857 AN: 67998

Other (OTH) AF: 0.0791 AC: 167 AN: 2110

Alfa AF: 0.0630 Hom.: 1175

Bravo AF: 0.0851

TwinsUK AF: 0.0577 AC: 214

ALSPAC AF: 0.0646 AC: 249

ESP6500AA AF: 0.145 AC: 638

ESP6500EA AF: 0.0566 AC: 487

ExAC AF: 0.0548 AC: 6652

Asia WGS AF: 0.0300 AC: 105 AN: 3478

EpiCase AF: 0.0514

EpiControl AF: 0.0562

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.30
DANN	Benign	0.59
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.30	.;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		-0.74
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.042
Sift	Benign	0.23	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.021
MPC		0.012
ClinPred		0.0080	T
GERP RS		-8.0
PromoterAI		0.031	Neutral
Varity_R		0.023
gMVP		0.31
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1442138; hg19: chr4-90816294; COSMIC: COSV53337317;