NM_005558.4:c.728T>C

Variant names:

• chr1-201386633-A-G
• rs12088790
• NM_005558.4:c.728T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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 0.11 (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
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005558.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAD1	NM_005558.4	MANE Select	c.728T>C	p.Leu243Pro	missense	Exon 3 of 10	NP_005549.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAD1	ENST00000391967.7	TSL:1 MANE Select	c.728T>C	p.Leu243Pro	missense	Exon 3 of 10	ENSP00000375829.2
	LAD1	ENST00000367313.4	TSL:1	c.770T>C	p.Leu257Pro	missense	Exon 3 of 10	ENSP00000356282.3
	LAD1	ENST00000632743.1	TSL:4	c.*214T>C		downstream_gene	N/A	ENSP00000487828.1

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

GnomAD2 exomes AF: 0.0505 AC: 12676 AN: 251160 AF XY: 0.0451

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 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

African (AFR) AF: 0.335 AC: 11224 AN: 33476

American (AMR) AF: 0.0318 AC: 1422 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0789 AC: 2063 AN: 26136

East Asian (EAS) AF: 0.0279 AC: 1107 AN: 39700

South Asian (SAS) AF: 0.0327 AC: 2822 AN: 86258

European-Finnish (FIN) AF: 0.0326 AC: 1742 AN: 53416

Middle Eastern (MID) AF: 0.0777 AC: 448 AN: 5768

European-Non Finnish (NFE) AF: 0.0239 AC: 26603 AN: 1111998

Other (OTH) AF: 0.0515 AC: 3113 AN: 60396

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

African (AFR) AF: 0.327 AC: 13547 AN: 41476

American (AMR) AF: 0.0524 AC: 801 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0851 AC: 295 AN: 3468

East Asian (EAS) AF: 0.0313 AC: 162 AN: 5178

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4830

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10620

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1764 AN: 68014

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0535 Hom.: 2468

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 v4.9

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
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-1.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.010
Sift	Benign	0.43	T
Sift4G	Benign	0.35	T
Polyphen		0.0040	B
Vest4		0.035
MPC		0.17
ClinPred		0.0035	T
GERP RS		0.80
Varity_R		0.026
gMVP		0.024
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12088790; hg19: chr1-201355761; COSMIC: COSV108220199; COSMIC: COSV108220199;