7-16557378-C-A

Variant names:

• chr7-16557378-C-A
• rs548865378
• NM_001195280.2:c.253C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001195280.2(LRRC72):​c.253C>A​(p.Leu85Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000082 in 1,316,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: LRRC72 NM_001195280.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.161
• Publications: 1 publications found

Genes affected

LRRC72 (HGNC:42972): (leucine rich repeat containing 72)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012157768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC72	NM_001195280.2	c.253C>A	p.Leu85Ile	missense_variant	Exon 4 of 9	ENST00000401542.3	NP_001182209.1
LRRC72	XM_011515057.2	c.253C>A	p.Leu85Ile	missense_variant	Exon 4 of 10		XP_011513359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC72	ENST00000401542.3	c.253C>A	p.Leu85Ile	missense_variant	Exon 4 of 9	5	NM_001195280.2	ENSP00000384971.2

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 151916 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000740 AC: 6 AN: 81122 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 39 AN: 1164258 Hom.: 0 Cov.: 19 AF XY: 0.0000245 AC XY: 14 AN XY: 572210

African (AFR) AF: 0.00144 AC: 35 AN: 24366

American (AMR) AF: 0.00 AC: 0 AN: 18010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20344

East Asian (EAS) AF: 0.00 AC: 0 AN: 28572

South Asian (SAS) AF: 0.00 AC: 0 AN: 45018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4970

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 933032

Other (OTH) AF: 0.0000625 AC: 3 AN: 47974

GnomAD4 genome AF: 0.000454 AC: 69 AN: 152024 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74314

African (AFR) AF: 0.00164 AC: 68 AN: 41528

American (AMR) AF: 0.0000656 AC: 1 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10516

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000403 Hom.: 0

Bravo AF: 0.000529

ExAC AF: 0.000205 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253C>A (p.L85I) alteration is located in exon 4 (coding exon 4) of the LRRC72 gene. This alteration results from a C to A substitution at nucleotide position 253, causing the leucine (L) at amino acid position 85 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.16
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.066	T
Sift4G	Pathogenic	0.0	D
Vest4		0.33
MVP		0.32
ClinPred		0.077	T
GERP RS		-1.9
Varity_R		0.085
gMVP		0.18
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs548865378; hg19: chr7-16597003; COSMIC: COSV69129473;