14-76844896-T-G

Position:

• chr14-76844896-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001385106.1(LRRC74A):​c.671T>G​(p.Met224Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000057 in 1,403,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: LRRC74A NM_001385106.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.47

Genes affected

LRRC74A (HGNC:23346): (leucine rich repeat containing 74A)

LRRC74A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC74A	NM_001385106.1	c.671T>G	p.Met224Arg	missense_variant	7/14	ENST00000689127.1	NP_001372035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC74A	ENST00000689127.1	c.671T>G	p.Met224Arg	missense_variant	7/14		NM_001385106.1	ENSP00000509938.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249586 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000570 AC: 8 AN: 1403038 Hom.: 0 Cov.: 27 AF XY: 0.00000713 AC XY: 5 AN XY: 701252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000897

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.44e-7

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.722T>G (p.M241R) alteration is located in exon 7 (coding exon 7) of the LRRC74A gene. This alteration results from a T to G substitution at nucleotide position 722, causing the methionine (M) at amino acid position 241 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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.64	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.31
Sift	Benign	0.087	T
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.70		Gain of catalytic residue at N245 (P = 0);
MVP		0.67
MPC		0.23
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.33		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200597036; hg19: chr14-77311239; COSMIC: COSV53608796; COSMIC: COSV53608796;