Genetic Variant NM_001195545.2:c.-286G>T (chr17-39927703-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_001195545.2(LRRC3C):c.-286G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 985,192 control chromosomes in the GnomAD database, including 14 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.

Frequency

Genomes: 𝑓 0.0064 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00065 ( 6 hom. )

Consequence

LRRC3C
NM_001195545.2 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.288

Publications

3 publications found

Variant links:

Genes affected

LRRC3C (HGNC:40034): (leucine rich repeat containing 3C) 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]

LRRC3C links:

ORMDL3 (HGNC:16038): (ORMDL sphingolipid biosynthesis regulator 3) Involved in ceramide metabolic process. Acts upstream of or within several processes, including negative regulation of B cell apoptotic process; negative regulation of ceramide biosynthetic process; and positive regulation of protein localization to nucleus. Located in endoplasmic reticulum. Part of SPOTS complex. [provided by Alliance of Genome Resources, Apr 2022]

ORMDL3 links:

ENSG00000264968 (HGNC:):

ENSG00000264968 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00643 (977/151984) while in subpopulation AFR AF = 0.0219 (905/41298). AF 95% confidence interval is 0.0207. There are 8 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC3C	NM_001195545.2 link	c.-286G>T		upstream_gene_variant		ENST00000377924.6	NP_001182474.1	A6NJW4
ORMDL3	NM_139280.4 link	c.-242C>A		upstream_gene_variant		ENST00000304046.7	NP_644809.1	Q8N138-1A0A024R1W6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC3C	ENST00000377924.6 link	c.-286G>T		upstream_gene_variant		3	NM_001195545.2	ENSP00000367157.4		A6NJW4
ORMDL3	ENST00000304046.7 link	c.-242C>A		upstream_gene_variant		1	NM_139280.4	ENSP00000304858.2		Q8N138-1

Frequencies

GnomAD3 genomes

AF:

0.00642

AC:

975

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00431

GnomAD4 exome

AF:

0.000652

AC:

543

AN:

833208

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

235

AN XY:

384830

show subpopulations

African (AFR)

AF:

0.0286

AC:

449

AN:

15702

American (AMR)

AF:

0.00507

AC:

AN:

986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5154

East Asian (EAS)

AF:

0.00

AC:

AN:

3632

South Asian (SAS)

AF:

0.00

AC:

AN:

16476

European-Finnish (FIN)

AF:

0.00

AC:

AN:

278

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

1624

European-Non Finnish (NFE)

AF:

0.0000709

AC:

AN:

762068

Other (OTH)

AF:

0.00121

AC:

AN:

27288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00643

AC:

977

AN:

151984

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

488

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0219

AC:

905

AN:

41298

American (AMR)

AF:

0.00327

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68012

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00729

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

5.7

(source)

DANN

Benign

0.78

PhyloP100

0.29

PromoterAI

0.032

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over