rs755718839

Variant names:

• chr6-43509628-G-T
• rs755718839
• NM_001012974.4:c.158C>A

Variant summary

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

The NM_001012974.4(LRRC73):​c.158C>A​(p.Ala53Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,450,472 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: 0.0000055 (0 hom.)
• Consequence: LRRC73 NM_001012974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• Publications: 0 publications found

Genes affected

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

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

ACMG classification

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	c.158C>A	p.Ala53Asp	missense_variant	Exon 1 of 6	ENST00000372441.2	NP_001012992.1
LRRC73	NM_001271882.2	c.-98+578C>A		intron_variant	Intron 1 of 5		NP_001258811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC73	ENST00000372441.2	c.158C>A	p.Ala53Asp	missense_variant	Exon 1 of 6	1	NM_001012974.4	ENSP00000361518.1
POLR1C	ENST00000428025.6	c.-277G>T		upstream_gene_variant		4		ENSP00000395401.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000273 AC: 6 AN: 220014 AF XY: 0.0000247

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

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: 0.000364

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1450472 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 721024

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.000162 AC: 7 AN: 43338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39402

South Asian (SAS) AF: 0.00 AC: 0 AN: 85122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4816

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108478

Other (OTH) AF: 0.0000167 AC: 1 AN: 59866

GnomAD4 genome Cov.: 33

Alfa AF: 0.000816 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000839 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158C>A (p.A53D) alteration is located in exon 1 (coding exon 1) of the LRRC73 gene. This alteration results from a C to A substitution at nucleotide position 158, causing the alanine (A) at amino acid position 53 to be replaced by an aspartic acid (D). 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	0.67
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.25
Sift	Benign	0.040	D
Sift4G	Benign	0.47	T
Polyphen		0.84	P
Vest4		0.63
MutPred		0.41		Loss of MoRF binding (P = 0.0808);
MVP		0.26
MPC		1.3
ClinPred		0.29	T
GERP RS		4.1
PromoterAI		-0.036	Neutral
Varity_R		0.48
gMVP		0.69
Mutation Taster		=46/54	disease causing

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: rs755718839; hg19: chr6-43477366;