3-3845037-C-A

Variant names:

• chr3-3845037-C-A
• rs3749350
• NM_020873.7:c.396C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_020873.7(LRRN1):​c.396C>A​(p.Thr132Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,828 control chromosomes in the GnomAD database, including 24,228 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T132T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.21 (4301 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19927 hom.)
• Consequence: LRRN1 NM_020873.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25
• Publications: 14 publications found

Genes affected

LRRN1 (HGNC:20980): (leucine rich repeat neuronal 1) Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SUMF1 (HGNC:20376): (sulfatase modifying factor 1) This gene encodes an enzyme that catalyzes the hydrolysis of sulfate esters by oxidizing a cysteine residue in the substrate sulfatase to an active site 3-oxoalanine residue, which is also known as C-alpha-formylglycine. Mutations in this gene cause multiple sulfatase deficiency, a lysosomal storage disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

SUMF1 Gene-Disease associations (from GenCC):

• mucosulfatidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRN1	NM_020873.7	c.396C>A	p.Thr132Thr	synonymous_variant	Exon 2 of 2	ENST00000319331.4	NP_065924.3
LRRN1	NM_001324188.2	c.396C>A	p.Thr132Thr	synonymous_variant	Exon 3 of 3		NP_001311117.1
LRRN1	NM_001324189.2	c.396C>A	p.Thr132Thr	synonymous_variant	Exon 3 of 3		NP_001311118.1
LRRN1	XM_047448644.1	c.396C>A	p.Thr132Thr	synonymous_variant	Exon 2 of 2		XP_047304600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRN1	ENST00000319331.4	c.396C>A	p.Thr132Thr	synonymous_variant	Exon 2 of 2	1	NM_020873.7	ENSP00000314901.3
SUMF1	ENST00000448413.5	n.1192-17528G>T		intron_variant	Intron 9 of 12	2		ENSP00000404384.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32004 AN: 151928 Hom.: 4287 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.0802

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.188 AC: 47269 AN: 251112 AF XY: 0.181

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.434

Gnomad FIN exome AF: 0.0825

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.150 AC: 219014 AN: 1461782 Hom.: 19927 Cov.: 75 AF XY: 0.150 AC XY: 109267 AN XY: 727212

African (AFR) AF: 0.372 AC: 12448 AN: 33476

American (AMR) AF: 0.244 AC: 10916 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4458 AN: 26136

East Asian (EAS) AF: 0.413 AC: 16378 AN: 39676

South Asian (SAS) AF: 0.221 AC: 19065 AN: 86252

European-Finnish (FIN) AF: 0.0857 AC: 4577 AN: 53418

Middle Eastern (MID) AF: 0.177 AC: 1023 AN: 5766

European-Non Finnish (NFE) AF: 0.125 AC: 139498 AN: 1111944

Other (OTH) AF: 0.176 AC: 10651 AN: 60392

GnomAD4 genome AF: 0.211 AC: 32063 AN: 152046 Hom.: 4301 Cov.: 32 AF XY: 0.212 AC XY: 15790 AN XY: 74336

African (AFR) AF: 0.360 AC: 14924 AN: 41430

American (AMR) AF: 0.232 AC: 3545 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3472

East Asian (EAS) AF: 0.413 AC: 2133 AN: 5160

South Asian (SAS) AF: 0.217 AC: 1044 AN: 4814

European-Finnish (FIN) AF: 0.0802 AC: 848 AN: 10578

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.124 AC: 8459 AN: 67992

Other (OTH) AF: 0.223 AC: 470 AN: 2110

Alfa AF: 0.147 Hom.: 3440

Bravo AF: 0.232

Asia WGS AF: 0.340 AC: 1183 AN: 3476

EpiCase AF: 0.125

EpiControl AF: 0.124

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.082
DANN	Benign	0.74
PhyloP100		-3.2
Mutation Taster		=100/0	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: rs3749350; hg19: chr3-3886721; COSMIC: COSV60012751; COSMIC: COSV60012751;