chr7-16527002-T-G

Variant names:

• chr7-16527002-T-G
• rs775403272
• NM_001195280.2:c.50T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195280.2(LRRC72):​c.50T>G​(p.Leu17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,539,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: LRRC72 NM_001195280.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.99
• Publications: 0 publications found

Genes affected

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

SOSTDC1 (HGNC:21748): (sclerostin domain containing 1) This gene is a member of the sclerostin family and encodes an N-glycosylated, secreted protein with a C-terminal cystine knot-like domain. This protein functions as a bone morphogenetic protein (BMP) antagonist. Specifically, it directly associates with BMPs, prohibiting them from binding their receptors, thereby regulating BMP signaling during cellular proliferation, differentiation, and programmed cell death. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13160008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC72	NM_001195280.2	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 9	ENST00000401542.3	NP_001182209.1
LRRC72	XM_011515057.2	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 10		XP_011513359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC72	ENST00000401542.3	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 9	5	NM_001195280.2	ENSP00000384971.2
LRRC72	ENST00000382124.7	n.50T>G		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000371558.3
LRRC72	ENST00000482711.1	n.113T>G		non_coding_transcript_exon_variant	Exon 1 of 3	2
SOSTDC1	ENST00000396652.1	c.-320+3185A>C		intron_variant	Intron 1 of 4	2		ENSP00000379889.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000937 AC: 13 AN: 1387568 Hom.: 0 Cov.: 30 AF XY: 0.00000730 AC XY: 5 AN XY: 684792

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1078902

Other (OTH) AF: 0.00 AC: 0 AN: 57928

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50T>G (p.L17R) alteration is located in exon 1 (coding exon 1) of the LRRC72 gene. This alteration results from a T to G substitution at nucleotide position 50, causing the leucine (L) at amino acid position 17 to be replaced by an arginine (R). 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	0.060
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.062
DANN	Benign	0.94
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-2.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.050
Sift	Uncertain	0.020	D
Sift4G	Benign	0.079	T
Vest4		0.15
MutPred		0.52		Gain of disorder (P = 0.0158);
MVP		0.28
ClinPred		0.078	T
GERP RS		-6.4
PromoterAI		-0.016	Neutral
Varity_R		0.16
gMVP		0.20
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

Other links and lift over

dbSNP: rs775403272; hg19: chr7-16566627;