8-144520374-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014665.4(LRRC14):c.466G>A(p.Ala156Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 1,458,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: LRRC14 NM_014665.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.166

Genes affected

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05789131).
• BP6: Variant 8-144520374-G-A is Benign according to our data. Variant chr8-144520374-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2566968.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC14	NM_014665.4	c.466G>A	p.Ala156Thr	missense_variant	3/4	ENST00000292524.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC14	ENST00000292524.6	c.466G>A	p.Ala156Thr	missense_variant	3/4	1	NM_014665.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 245890 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133548

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1458012 Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15 AN XY: 725334

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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: 0.0000297

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000628 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.1
Dann	Benign	0.77
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.47	T;.;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.058	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.55	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0020	.;B;B;.
Vest4		0.10, 0.10
MVP		0.13
MPC		0.42
ClinPred		0.027	T
GERP RS		0.14
Varity_R		0.024
gMVP		0.17

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: rs373485047; hg19: chr8-145745758; COSMIC: COSV99468039; COSMIC: COSV99468039;