Genetic Variant NM_001385106.1:c.1298T>C (chr14-76866065-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001385106.1(LRRC74A):c.1298T>C(p.Val433Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,555,352 control chromosomes in the GnomAD database, including 81,092 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6694 hom., cov: 32)

Exomes 𝑓: 0.32 ( 74398 hom. )

Consequence

LRRC74A
NM_001385106.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.322

Publications

24 publications found

Variant links:

Genes affected

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

LRRC74A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041403174).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC74A	NM_001385106.1 link	c.1298T>C	p.Val433Ala	missense_variant	Exon 12 of 14	ENST00000689127.1	NP_001372035.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC74A	ENST00000689127.1 link	c.1298T>C	p.Val433Ala	missense_variant	Exon 12 of 14		NM_001385106.1	ENSP00000509938.1		A0A8I5KW16

Frequencies

GnomAD3 genomes

AF:

0.290

AC:

44083

AN:

151878

Hom.:

6689

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.293

Gnomad ASJ

AF:

0.333

Gnomad EAS

AF:

0.0876

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.330

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.342

Gnomad OTH

AF:

0.304

GnomAD2 exomes

AF:

0.285

AC:

62933

AN:

220748

AF XY:

0.286

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.310

Gnomad EAS exome

AF:

0.0916

Gnomad FIN exome

AF:

0.334

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.307

GnomAD4 exome

AF:

0.320

AC:

448760

AN:

1403356

Hom.:

74398

Cov.:

AF XY:

0.317

AC XY:

221285

AN XY:

698344

show subpopulations

African (AFR)

AF:

0.216

AC:

7005

AN:

32438

American (AMR)

AF:

0.278

AC:

11589

AN:

41638

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

8202

AN:

25644

East Asian (EAS)

AF:

0.0820

AC:

3204

AN:

39070

South Asian (SAS)

AF:

0.215

AC:

17703

AN:

82512

European-Finnish (FIN)

AF:

0.333

AC:

17445

AN:

52368

Middle Eastern (MID)

AF:

0.286

AC:

1623

AN:

5680

European-Non Finnish (NFE)

AF:

0.342

AC:

364035

AN:

1065410

Other (OTH)

AF:

0.306

AC:

17954

AN:

58596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13881

27762

41644

55525

69406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11420

22840

34260

45680

57100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.290

AC:

44101

AN:

151996

Hom.:

6694

Cov.:

AF XY:

0.286

AC XY:

21237

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.224

AC:

9297

AN:

41472

American (AMR)

AF:

0.294

AC:

4480

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

1156

AN:

3472

East Asian (EAS)

AF:

0.0878

AC:

454

AN:

5172

South Asian (SAS)

AF:

0.196

AC:

943

AN:

4816

European-Finnish (FIN)

AF:

0.330

AC:

3481

AN:

10562

Middle Eastern (MID)

AF:

0.301

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.342

AC:

23254

AN:

67932

Other (OTH)

AF:

0.302

AC:

636

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1642

3284

4925

6567

8209

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.317

Hom.:

32315

Bravo

AF:

0.284

TwinsUK

AF:

0.344

AC:

1276

ALSPAC

AF:

0.346

AC:

1334

ESP6500AA

AF:

0.218

AC:

905

ESP6500EA

AF:

0.339

AC:

2856

ExAC

AF:

0.268

AC:

32267

Asia WGS

AF:

0.178

AC:

621

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.63

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.020

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00095

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.92

PhyloP100

0.32

PROVEAN

Benign

1.8

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.011

MPC

0.035

ClinPred

0.00091

GERP RS

0.54

Varity_R

0.023

gMVP

0.33

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over