1-201386394-T-C

Position:

• chr1-201386394-T-C

Variant summary

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

The ENST00000391967.7(LAD1):​c.967A>G​(p.Lys323Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,518,574 control chromosomes in the GnomAD database, including 195,356 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 0.57 (26695 hom., cov: 32)
  • Exomes 𝑓: 0.49 (168661 hom.)
• Consequence: LAD1 ENST00000391967.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16

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=7.42325E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAD1	NM_005558.4	c.967A>G	p.Lys323Glu	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.967A>G	p.Lys323Glu	missense_variant	3/10	1	NM_005558.4	ENSP00000375829	P3
LAD1	ENST00000367313.4	c.1009A>G	p.Lys337Glu	missense_variant	3/10	1		ENSP00000356282	A2

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86921 AN: 151974 Hom.: 26662 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.583

GnomAD3 exomes AF: 0.498 AC: 84869 AN: 170284 Hom.: 22129 AF XY: 0.489 AC XY: 43762 AN XY: 89558

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.537

Gnomad EAS exome AF: 0.520

Gnomad SAS exome AF: 0.381

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.493 AC: 673277 AN: 1366482 Hom.: 168661 Cov.: 49 AF XY: 0.489 AC XY: 327776 AN XY: 670058

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.539

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.503

GnomAD4 genome AF: 0.572 AC: 86997 AN: 152092 Hom.: 26695 Cov.: 32 AF XY: 0.565 AC XY: 42033 AN XY: 74366

Gnomad4 AFR AF: 0.811

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.478

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.582

Alfa AF: 0.506 Hom.: 38127

Bravo AF: 0.583

TwinsUK AF: 0.498 AC: 1848

ALSPAC AF: 0.491 AC: 1891

ESP6500AA AF: 0.802 AC: 3531

ESP6500EA AF: 0.489 AC: 4209

ExAC AF: 0.480 AC: 55818

Asia WGS AF: 0.487 AC: 1693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.23
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.19	T;T
MetaRNN	Benign	7.4e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.038
MPC		0.15
ClinPred		0.0070	T
GERP RS		1.6
Varity_R		0.047
gMVP		0.051

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4128458; hg19: chr1-201355522; COSMIC: COSV66212460; COSMIC: COSV66212460;