4-122187460-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001384125.1(BLTP1):c.575C>G(p.Pro192Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,611,974 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (4 hom.)
• Consequence: BLTP1 NM_001384125.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.54

Genes affected

BLTP1 (HGNC:26953): (bridge-like lipid transfer protein family member 1) This gene is located on the long arm of chromosome 4 in a region that is associated with susceptibility to celiac disease. The encoded protein is similar to a Chinese hamster protein that is associated with spermatocyte and adipocyte differentiation. The C-terminus of the protein is also similar to a Caenorhabditis elegans protein that plays a role in lipid storage. In mammals, this protein is thought to function in the regulation of epithelial growth and differentiation, and in tumor development. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BLTP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.00586161).
• BP6: Variant 4-122187460-C-G is Benign according to our data. Variant chr4-122187460-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 809676.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000414 (63/152104) while in subpopulation EAS AF= 0.00694 (36/5190). AF 95% confidence interval is 0.00515. There are 1 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLTP1	NM_001384125.1	c.575C>G	p.Pro192Arg	missense_variant	8/88	ENST00000679879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLTP1	ENST00000679879.1	c.575C>G	p.Pro192Arg	missense_variant	8/88		NM_001384125.1	A2

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 151986 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00673

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000478 AC: 119 AN: 248794 Hom.: 2 AF XY: 0.000422 AC XY: 57 AN XY: 135002

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00596

Gnomad SAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1459870 Hom.: 4 Cov.: 31 AF XY: 0.000136 AC XY: 99 AN XY: 726278

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00316

Gnomad4 SAS exome AF: 0.000291

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000995

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152104 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74350

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00694

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000819 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2019

- -

BLTP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Alkuraya-Kucinskas syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Alkuraya-Kucinskas syndrome (MIM#617822). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Alkuraya-Kucinskas syndrome (present in gnomAD (v2) 127 heterozygotes, 2 homozygotes). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. The variant has previously been classified as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.0090	T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.52	T;T
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.54	P;P
Vest4		0.66
MVP		0.74
MPC		1.3
ClinPred		0.10	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs188182890; hg19: chr4-123108615;