14-23140574-G-A

Variant names:

• chr14-23140574-G-A
• rs199753830
• NM_012244.4:c.685C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012244.4(SLC7A8):​c.685C>T​(p.Pro229Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P229A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC7A8 NM_012244.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21
• Publications: 0 publications found

Genes affected

SLC7A8 (HGNC:11066): (solute carrier family 7 member 8) Enables several functions, including neutral amino acid transmembrane transporter activity; thyroid hormone transmembrane transporter activity; and toxin transmembrane transporter activity. Involved in L-alanine import across plasma membrane; L-leucine import across plasma membrane; and thyroid hormone transport. Located in plasma membrane. Part of basolateral plasma membrane and microvillus membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012244.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A8	NM_012244.4	MANE Select	c.685C>T	p.Pro229Ser	missense	Exon 5 of 11	NP_036376.2
	SLC7A8	NM_001267036.1		c.370C>T	p.Pro124Ser	missense	Exon 3 of 9	NP_001253965.1	Q9UHI5-4
	SLC7A8	NM_182728.3		c.76C>T	p.Pro26Ser	missense	Exon 3 of 9	NP_877392.1	Q9UHI5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A8	ENST00000316902.12	TSL:1 MANE Select	c.685C>T	p.Pro229Ser	missense	Exon 5 of 11	ENSP00000320378.7	Q9UHI5-1
	SLC7A8	ENST00000453702.5	TSL:1	c.76C>T	p.Pro26Ser	missense	Exon 3 of 9	ENSP00000391577.1	Q9UHI5-2
	SLC7A8	ENST00000469263.5	TSL:1	c.685C>T	p.Pro229Ser	missense	Exon 5 of 6	ENSP00000435114.1	E9PLV9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.30	N
PhyloP100		5.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.43
Sift	Benign	0.43	T
Sift4G	Benign	0.37	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.47		Gain of glycosylation at P229 (P = 0.0317)
MVP		0.98
MPC		0.28
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.072
gMVP		0.73
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs199753830; hg19: chr14-23609783;