rs12088790

Positions:

• chr1-201386633-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005558.4(LAD1):​c.728T>C​(p.Leu243Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,614,078 control chromosomes in the GnomAD database, including 4,935 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (2369 hom., cov: 33)
  • Exomes 𝑓: 0.035 (2566 hom.)
• Consequence: LAD1 NM_005558.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84

Genes affected

LAD1 (HGNC:6472): (ladinin 1) The protein encoded by this gene may be an anchoring filament that is a component of basement membranes. It may contribute to the stability of the association of the epithelial layers with the underlying mesenchyme. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038383007).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAD1	NM_005558.4	c.728T>C	p.Leu243Pro	missense_variant	3/10	ENST00000391967.7	NP_005549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAD1	ENST00000391967.7	c.728T>C	p.Leu243Pro	missense_variant	3/10	1	NM_005558.4	ENSP00000375829.2
LAD1	ENST00000367313.4	c.770T>C	p.Leu257Pro	missense_variant	3/10	1		ENSP00000356282.3

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17238 AN: 152088 Hom.: 2355 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0851

Gnomad EAS AF: 0.0314

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0746

GnomAD3 exomes AF: 0.0505 AC: 12676 AN: 251160 Hom.: 1092 AF XY: 0.0451 AC XY: 6127 AN XY: 135822

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0780

Gnomad EAS exome AF: 0.0284

Gnomad SAS exome AF: 0.0315

Gnomad FIN exome AF: 0.0339

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0436

GnomAD4 exome AF: 0.0346 AC: 50544 AN: 1461872 Hom.: 2566 Cov.: 46 AF XY: 0.0337 AC XY: 24526 AN XY: 727242

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.0318

Gnomad4 ASJ exome AF: 0.0789

Gnomad4 EAS exome AF: 0.0279

Gnomad4 SAS exome AF: 0.0327

Gnomad4 FIN exome AF: 0.0326

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0515

GnomAD4 genome AF: 0.114 AC: 17284 AN: 152206 Hom.: 2369 Cov.: 33 AF XY: 0.112 AC XY: 8328 AN XY: 74420

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.0524

Gnomad4 ASJ AF: 0.0851

Gnomad4 EAS AF: 0.0313

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0752

Alfa AF: 0.0471 Hom.: 957

Bravo AF: 0.126

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.330 AC: 1454

ESP6500EA AF: 0.0292 AC: 251

ExAC AF: 0.0554 AC: 6728

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0298

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.49
DEOGEN2	Benign	0.038	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.0	N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.010
Sift	Benign	0.43	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0040	B;B
Vest4		0.035
MPC		0.17
ClinPred		0.0035	T
GERP RS		0.80
Varity_R		0.026
gMVP		0.024

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12088790; hg19: chr1-201355761;