3-3845037-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020873.7(LRRN1):​c.396C>T​(p.Thr132Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000957 in 1,613,926 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: LRRN1 NM_020873.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.25

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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-3845037-C-T is Benign according to our data. Variant chr3-3845037-C-T is described in ClinVar as [Benign]. Clinvar id is 716843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00529 (805/152080) while in subpopulation AFR AF = 0.0188 (779/41450). AF 95% confidence interval is 0.0177. There are 9 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 805 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRN1	NM_020873.7	c.396C>T	p.Thr132Thr	synonymous_variant	Exon 2 of 2	ENST00000319331.4	NP_065924.3
LRRN1	NM_001324188.2	c.396C>T	p.Thr132Thr	synonymous_variant	Exon 3 of 3		NP_001311117.1
LRRN1	NM_001324189.2	c.396C>T	p.Thr132Thr	synonymous_variant	Exon 3 of 3		NP_001311118.1
LRRN1	XM_047448644.1	c.396C>T	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>T	p.Thr132Thr	synonymous_variant	Exon 2 of 2	1	NM_020873.7	ENSP00000314901.3
SUMF1	ENST00000448413.5	n.1192-17528G>A		intron_variant	Intron 9 of 12	2		ENSP00000404384.1

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 806 AN: 151962 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

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: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00148 AC: 372 AN: 251112 AF XY: 0.00106

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000506 AC: 740 AN: 1461846 Hom.: 4 Cov.: 75 AF XY: 0.000437 AC XY: 318 AN XY: 727230

African (AFR) AF: 0.0188 AC: 628 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111996

Other (OTH) AF: 0.000695 AC: 42 AN: 60394

GnomAD4 genome AF: 0.00529 AC: 805 AN: 152080 Hom.: 9 Cov.: 32 AF XY: 0.00492 AC XY: 366 AN XY: 74356

African (AFR) AF: 0.0188 AC: 779 AN: 41450

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67996

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.0000193 Hom.: 3440

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.50
DANN	Benign	0.85
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs3749350; hg19: chr3-3886721;