6-43509763-A-G

Variant names:

Variant summary

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

The NM_001012974.4(LRRC73):c.23T>C(p.Ile8Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,429,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

LRRC73
NM_001012974.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.70

Publications

0 publications found

Variant links:

Genes affected

LRRC73 (HGNC:21375): (leucine rich repeat containing 73)

LRRC73 links:

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

POLR1C Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 11
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Treacher Collins syndrome 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Treacher-Collins syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC73	NM_001012974.4 link	c.23T>C	p.Ile8Thr	missense_variant	Exon 1 of 6	ENST00000372441.2	NP_001012992.1	Q5JTD7
LRRC73	NM_001271882.2 link	c.-98+443T>C		intron_variant	Intron 1 of 5		NP_001258811.1	Q5JTD7Q3B825

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRC73	ENST00000372441.2 link	c.23T>C	p.Ile8Thr	missense_variant	Exon 1 of 6	1	NM_001012974.4	ENSP00000361518.1	Q5JTD7
POLR1C	ENST00000428025.6 link	c.-142A>G		5_prime_UTR_variant	Exon 1 of 6	4		ENSP00000395401.2	D6RDJ3
POLR1C	ENST00000646188.1 link	c.-466A>G		upstream_gene_variant				ENSP00000496001.1	A0A2R8YEY5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000494

AC:

AN:

202580

AF XY:

0.00000886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000305

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:

7.00e-7

AC:

AN:

1429386

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709776

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32996

American (AMR)

AF:

0.0000230

AC:

AN:

43508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24920

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

82844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104280

Other (OTH)

AF:

0.00

AC:

AN:

59404

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.23T>C (p.I8T) alteration is located in exon 1 (coding exon 1) of the LRRC73 gene. This alteration results from a T to C substitution at nucleotide position 23, causing the isoleucine (I) at amino acid position 8 to be replaced by a threonine (T). 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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.088

Eigen

Benign

0.084

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

PhyloP100

6.7

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.33

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.15

Vest4

0.80

MutPred

0.54

Loss of stability (P = 0.0281);

MVP

0.19

MPC

1.6

ClinPred

0.95

GERP RS

3.8

PromoterAI

-0.026

Neutral

(source)

Varity_R

0.22

gMVP

0.73

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-43509763-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over