chr6-43509775-C-G

Variant names:

• chr6-43509775-C-G
• NM_001012974.4:c.11G>C

Variant summary

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

The NM_001012974.4(LRRC73):​c.11G>C​(p.Ser4Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRC73 NM_001012974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12373197).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC73	NM_001012974.4	MANE Select	c.11G>C	p.Ser4Thr	missense	Exon 1 of 6	NP_001012992.1	Q5JTD7
	LRRC73	NM_001271882.2		c.-98+431G>C		intron	N/A	NP_001258811.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC73	ENST00000372441.2	TSL:1 MANE Select	c.11G>C	p.Ser4Thr	missense	Exon 1 of 6	ENSP00000361518.1	Q5JTD7
	LRRC73	ENST00000899667.1		c.11G>C	p.Ser4Thr	missense	Exon 1 of 5	ENSP00000569726.1
	POLR1C	ENST00000428025.6	TSL:4	c.-130C>G		5_prime_UTR	Exon 1 of 6	ENSP00000395401.2	D6RDJ3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.11
Sift	Uncertain	0.021	D
Sift4G	Benign	0.077	T
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.31		Gain of sheet (P = 0.0149)
MVP		0.043
MPC		0.73
ClinPred		0.70	D
GERP RS		3.8
PromoterAI		0.044	Neutral
Varity_R		0.25
gMVP		0.36
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

hg19: chr6-43477513;