chr4-185378831-G-A

Variant names:

• chr4-185378831-G-A
• rs1288548
• ENST00000328559.11:c.-645C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018409.4(LRP2BP):​c.-645C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 985,142 control chromosomes in the GnomAD database, including 20,340 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4069 hom., cov: 32)
  • Exomes 𝑓: 0.20 (16271 hom.)
• Consequence: LRP2BP NM_018409.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510
• Publications: 10 publications found

Genes affected

LRP2BP (HGNC:25434): (LRP2 binding protein) Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SNX25 (HGNC:21883): (sorting nexin 25) Predicted to enable type I transforming growth factor beta receptor binding activity. Involved in negative regulation of pathway-restricted SMAD protein phosphorylation; negative regulation of transforming growth factor beta receptor signaling pathway; and receptor catabolic process. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018409.4. 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
	LRP2BP	NM_001377440.1	MANE Select	c.-21-624C>T		intron	N/A	NP_001364369.1
	LRP2BP	NM_018409.4		c.-645C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_060879.2
	LRP2BP	NM_018409.4		c.-645C>T		5_prime_UTR	Exon 1 of 8	NP_060879.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2BP	ENST00000328559.11	TSL:1	c.-645C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000332681.7
	LRP2BP	ENST00000510776.5	TSL:1	c.-1785C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000424610.1
	LRP2BP	ENST00000328559.11	TSL:1	c.-645C>T		5_prime_UTR	Exon 1 of 8	ENSP00000332681.7

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33624 AN: 151952 Hom.: 4073 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.196 AC: 162900 AN: 833072 Hom.: 16271 Cov.: 31 AF XY: 0.196 AC XY: 75437 AN XY: 384694

African (AFR) AF: 0.355 AC: 5604 AN: 15784

American (AMR) AF: 0.247 AC: 244 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 1072 AN: 5152

East Asian (EAS) AF: 0.171 AC: 621 AN: 3630

South Asian (SAS) AF: 0.170 AC: 2792 AN: 16458

European-Finnish (FIN) AF: 0.159 AC: 44 AN: 276

Middle Eastern (MID) AF: 0.224 AC: 363 AN: 1620

European-Non Finnish (NFE) AF: 0.193 AC: 146766 AN: 761872

Other (OTH) AF: 0.198 AC: 5394 AN: 27294

GnomAD4 genome AF: 0.221 AC: 33628 AN: 152070 Hom.: 4069 Cov.: 32 AF XY: 0.218 AC XY: 16242 AN XY: 74352

African (AFR) AF: 0.319 AC: 13225 AN: 41430

American (AMR) AF: 0.224 AC: 3420 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3470

East Asian (EAS) AF: 0.173 AC: 895 AN: 5168

South Asian (SAS) AF: 0.163 AC: 785 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1390 AN: 10582

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12603 AN: 67996

Other (OTH) AF: 0.205 AC: 434 AN: 2112

Alfa AF: 0.199 Hom.: 3251

Bravo AF: 0.240

Asia WGS AF: 0.178 AC: 619 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.69
PhyloP100		0.51
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1288548; hg19: chr4-186299985;