3-169804064-C-T

Variant names:

• chr3-169804064-C-T
• rs746708653
• NM_001172779.2:c.646G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001172779.2(LRRC34):​c.646G>A​(p.Asp216Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,435,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LRRC34 NM_001172779.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

Genes affected

LRRC34 (HGNC:28408): (leucine rich repeat containing 34) Predicted to be involved in cell differentiation. Predicted to be located in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
LRRC34	NM_001172779.2	c.646G>A	p.Asp216Asn	missense_variant	Exon 6 of 11	ENST00000446859.7	NP_001166250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC34	ENST00000446859.7	c.646G>A	p.Asp216Asn	missense_variant	Exon 6 of 11	2	NM_001172779.2	ENSP00000414635.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000169 AC: 4 AN: 236306 Hom.: 0 AF XY: 0.0000235 AC XY: 3 AN XY: 127742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000232

Gnomad SAS 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: 0.00000279 AC: 4 AN: 1435316 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 713158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000773

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646G>A (p.D216N) alteration is located in exon 6 (coding exon 6) of the LRRC34 gene. This alteration results from a G to A substitution at nucleotide position 646, causing the aspartic acid (D) at amino acid position 216 to be replaced by an asparagine (N). 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	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.92	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.20
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.021	D;T;T
Polyphen		0.75	.;P;.
Vest4		0.75
MVP		0.51
MPC		0.38
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.36
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs746708653; hg19: chr3-169521852;