4-122175886-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BS1_Supporting

The NM_001384125.1(BLTP1):c.330A>C(p.Lys110Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000563 in 1,563,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: BLTP1 NM_001384125.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BLTP1
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000657 (10/152102) while in subpopulation AMR AF= 0.000524 (8/15274). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLTP1	NM_001384125.1	c.330A>C	p.Lys110Asn	missense_variant	6/88	ENST00000679879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLTP1	ENST00000679879.1	c.330A>C	p.Lys110Asn	missense_variant	6/88		NM_001384125.1	A2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000933 AC: 23 AN: 246550 Hom.: 0 AF XY: 0.0000822 AC XY: 11 AN XY: 133840

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.0000892

Gnomad OTH exome AF: 0.000841

GnomAD4 exome AF: 0.0000553 AC: 78 AN: 1410924 Hom.: 0 Cov.: 23 AF XY: 0.0000525 AC XY: 37 AN XY: 704986

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.0000506

Gnomad4 OTH exome AF: 0.0000852

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.0000994 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The c.330A>C (p.K110N) alteration is located in exon 4 (coding exon 4) of the KIAA1109 gene. This alteration results from a A to C substitution at nucleotide position 330, causing the lysine (K) at amino acid position 110 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.49		Loss of ubiquitination at K110 (P = 0.0283);Loss of ubiquitination at K110 (P = 0.0283);
MVP		0.47
MPC		1.5
ClinPred		0.077	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.16
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs756207682; hg19: chr4-123097041;