19-17489115-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198580.3(SLC27A1):ā€‹c.994A>Gā€‹(p.Thr332Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000124 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SLC27A1
NM_198580.3 missense, splice_region

Scores

10
8
1
Splicing: ADA: 0.4777
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.13
Variant links:
Genes affected
SLC27A1 (HGNC:10995): (solute carrier family 27 member 1) Enables biotin transmembrane transporter activity; efflux transmembrane transporter activity; and long-chain fatty acid transporter activity. Involved in several processes, including carboxylic acid transmembrane transport; glycerophospholipid biosynthetic process; and lipid transport across blood-brain barrier. Located in membrane. Part of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
PGLS-DT (HGNC:55274): (PGLS divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC27A1NM_198580.3 linkuse as main transcriptc.994A>G p.Thr332Ala missense_variant, splice_region_variant 6/12 ENST00000252595.12 NP_940982.1
PGLS-DTNR_147835.1 linkuse as main transcriptn.670-20T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC27A1ENST00000252595.12 linkuse as main transcriptc.994A>G p.Thr332Ala missense_variant, splice_region_variant 6/121 NM_198580.3 ENSP00000252595 P1Q6PCB7-1
PGLS-DTENST00000596643.5 linkuse as main transcriptn.670-20T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461678
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727144
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 19, 2024The c.994A>G (p.T332A) alteration is located in exon 6 (coding exon 6) of the SLC27A1 gene. This alteration results from a A to G substitution at nucleotide position 994, causing the threonine (T) at amino acid position 332 to be replaced by an alanine (A). 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
0.67
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.097
D
MutationAssessor
Pathogenic
3.8
H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.5
D;.
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;.
Vest4
0.98
MutPred
0.88
Loss of methylation at K328 (P = 0.0679);.;
MVP
0.90
MPC
1.2
ClinPred
1.0
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.69
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.48
dbscSNV1_RF
Benign
0.43
SpliceAI score (max)
0.25
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.25
Position offset: -11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1379997115; hg19: chr19-17599924; API