Genetic Variant SLC27A4:p.Gly209Cys (chr9-128348613-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005094.4(SLC27A4):c.625G>T(p.Gly209Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G209S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC27A4
NM_005094.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

0 publications found

Variant links:

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]

SLC27A4 Gene-Disease associations (from GenCC):

ichthyosis prematurity syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P

SLC27A4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.087828904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC27A4	NM_005094.4 link	c.625G>T	p.Gly209Cys	missense_variant	Exon 4 of 13	ENST00000300456.5	NP_005085.2	Q6P1M0-1A0A024R8D2
SLC27A4	XM_047422664.1 link	c.658G>T	p.Gly220Cys	missense_variant	Exon 4 of 13		XP_047278620.1
SLC27A4	XM_017014222.2 link	c.625G>T	p.Gly209Cys	missense_variant	Exon 5 of 14		XP_016869711.1	Q6P1M0-1A0A024R8D2
SLC27A4	XM_024447391.2 link	c.625G>T	p.Gly209Cys	missense_variant	Exon 5 of 14		XP_024303159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC27A4	ENST00000300456.5 link	c.625G>T	p.Gly209Cys	missense_variant	Exon 4 of 13	1	NM_005094.4	ENSP00000300456.3		Q6P1M0-1
SLC27A4	ENST00000372870.5 link	c.231+5332G>T		intron_variant	Intron 2 of 5	1		ENSP00000361961.1		Q6P1M0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727058

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.22

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.31

M_CAP

Benign

0.027

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.97

PhyloP100

1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.86

REVEL

Benign

0.027

Sift

Benign

0.037

Sift4G

Uncertain

0.050

Polyphen

0.066

Vest4

0.14

MutPred

0.43

Gain of catalytic residue at P208 (P = 0.0135);

MVP

0.49

MPC

0.30

ClinPred

0.17

GERP RS

0.64

Varity_R

0.10

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over