Genetic Variant LAMB4:p.Val591Phe (chr7-108079717-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_007356.3(LAMB4):c.1771G>T(p.Val591Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 1,611,290 control chromosomes in the GnomAD database, including 10,308 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.16 ( 3872 hom., cov: 32)

Exomes 𝑓: 0.075 ( 6436 hom. )

Consequence

LAMB4
NM_007356.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.256

Publications

17 publications found

Variant links:

Genes affected

LAMB4 (HGNC:6491): (laminin subunit beta 4) Predicted to be an extracellular matrix structural constituent. Predicted to be involved in several processes, including basement membrane assembly; cell migration; and substrate adhesion-dependent cell spreading. Predicted to be located in basement membrane; extracellular region; and membrane. Predicted to be part of laminin complex. [provided by Alliance of Genome Resources, Apr 2022]

LAMB4 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=0.0025619268).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB4	NM_007356.3 link	c.1771G>T	p.Val591Phe	missense_variant	Exon 15 of 34	ENST00000388781.8	NP_031382.2	A4D0S4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMB4	ENST00000388781.8 link	c.1771G>T	p.Val591Phe	missense_variant	Exon 15 of 34	1	NM_007356.3	ENSP00000373433.3	A4D0S4-1
LAMB4	ENST00000205386.8 link	c.1771G>T	p.Val591Phe	missense_variant	Exon 15 of 34	1		ENSP00000205386.4	A4D0S4-1
LAMB4	ENST00000418464.1 link	c.1771G>T	p.Val591Phe	missense_variant	Exon 15 of 18	1		ENSP00000402353.2	C9JMJ0
LAMB4	ENST00000475469.1 link	n.1855G>T		non_coding_transcript_exon_variant	Exon 15 of 23	2

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24723

AN:

151964

Hom.:

3862

Cov.:

show subpopulations

Gnomad AFR

AF:

0.411

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0767

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.0748

Gnomad FIN

AF:

0.0677

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0639

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.0886

AC:

21964

AN:

247896

AF XY:

0.0823

show subpopulations

Gnomad AFR exome

AF:

0.420

Gnomad AMR exome

AF:

0.0900

Gnomad ASJ exome

AF:

0.0796

Gnomad EAS exome

AF:

0.00770

Gnomad FIN exome

AF:

0.0621

Gnomad NFE exome

AF:

0.0643

Gnomad OTH exome

AF:

0.0776

GnomAD4 exome

AF:

0.0746

AC:

108808

AN:

1459208

Hom.:

6436

Cov.:

AF XY:

0.0736

AC XY:

53385

AN XY:

725772

show subpopulations

African (AFR)

AF:

0.430

AC:

14356

AN:

33404

American (AMR)

AF:

0.0906

AC:

4008

AN:

44220

Ashkenazi Jewish (ASJ)

AF:

0.0786

AC:

2049

AN:

26064

East Asian (EAS)

AF:

0.0141

AC:

558

AN:

39550

South Asian (SAS)

AF:

0.0751

AC:

6416

AN:

85470

European-Finnish (FIN)

AF:

0.0659

AC:

3517

AN:

53386

Middle Eastern (MID)

AF:

0.0944

AC:

544

AN:

5760

European-Non Finnish (NFE)

AF:

0.0647

AC:

71829

AN:

1111034

Other (OTH)

AF:

0.0917

AC:

5531

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

4960

9920

14880

19840

24800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2906

5812

8718

11624

14530

<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:

0.163

AC:

24769

AN:

152082

Hom.:

3872

Cov.:

AF XY:

0.157

AC XY:

11681

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.411

AC:

17028

AN:

41398

American (AMR)

AF:

0.106

AC:

1622

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0767

AC:

266

AN:

3466

East Asian (EAS)

AF:

0.00907

AC:

AN:

5180

South Asian (SAS)

AF:

0.0741

AC:

357

AN:

4820

European-Finnish (FIN)

AF:

0.0677

AC:

718

AN:

10598

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0639

AC:

4344

AN:

68020

Other (OTH)

AF:

0.135

AC:

285

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

870

1739

2609

3478

4348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.0929

Hom.:

5815

Bravo

AF:

0.179

TwinsUK

AF:

0.0674

AC:

250

ALSPAC

AF:

0.0654

AC:

252

ESP6500AA

AF:

0.396

AC:

1746

ESP6500EA

AF:

0.0673

AC:

579

ExAC

AF:

0.0942

AC:

11434

Asia WGS

AF:

0.0700

AC:

244

AN:

3478

EpiCase

AF:

0.0642

EpiControl

AF:

0.0645

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.71

.;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

-0.26

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.062

Sift

Benign

0.045

D;D;D

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.93

P;P;.

Vest4

0.14

MPC

0.26

ClinPred

0.024

GERP RS

1.5

Varity_R

0.13

gMVP

0.65

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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