9-128343125-A-G

Position:

• chr9-128343125-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005094.4(SLC27A4):​c.-6-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC27A4 NM_005094.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.84

Genes affected

SLC27A4 (HGNC:10998): (solute carrier family 27 member 4) This gene encodes a member of a family of fatty acid transport proteins, which are involved in translocation of long-chain fatty acids cross the plasma membrane. This protein is expressed at high levels on the apical side of mature enterocytes in the small intestine, and appears to be the principal fatty acid transporter in enterocytes. Clinical studies suggest this gene as a candidate gene for the insulin resistance syndrome. Mutations in this gene have been associated with ichthyosis prematurity syndrome. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-128343125-A-G is Pathogenic according to our data. Variant chr9-128343125-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1696265.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC27A4	NM_005094.4	c.-6-2A>G		splice_acceptor_variant, intron_variant		ENST00000300456.5	NP_005085.2
SLC27A4	XM_047422664.1	c.28-2A>G		splice_acceptor_variant, intron_variant			XP_047278620.1
SLC27A4	XM_017014222.2	c.-6-2A>G		splice_acceptor_variant, intron_variant			XP_016869711.1
SLC27A4	XM_024447391.2	c.-6-2A>G		splice_acceptor_variant, intron_variant			XP_024303159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC27A4	ENST00000300456.5	c.-6-2A>G		splice_acceptor_variant, intron_variant		1	NM_005094.4	ENSP00000300456.3
SLC27A4	ENST00000372870.5	c.77-2A>G		splice_acceptor_variant, intron_variant		1		ENSP00000361961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lamellar ichthyosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2022

Variant summary: SLC27A4 c.-6-2A>G alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. Theoretically, such an impact could result in the functional equivalent of a start loss variant due to the skipping of exon 2 bearing the ATG start codon. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249840 control chromosomes. To our knowledge, no occurrence of c.-6-2A>G in individuals affected with Lamellar Ichthyosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Benign	0.89
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-131105404;