7-74220217-G-T

Variant names:

• chr7-74220217-G-T
• NM_032464.3:c.228G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032464.3(LAT2):​c.228G>T​(p.Arg76Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAT2 NM_032464.3 missense, splice_region
• Scores: Splicing: ADA: 0.9858
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

Genes affected

LAT2 (HGNC:12749): (linker for activation of T cells family member 2) This gene is one of the contiguous genes at 7q11.23 commonly deleted in Williams syndrome, a multisystem developmental disorder. This gene consists of at least 14 exons, and its alternative splicing generates 3 transcript variants, all encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAT2	NM_032464.3	c.228G>T	p.Arg76Ser	missense_variant, splice_region_variant	Exon 7 of 14	ENST00000460943.6	NP_115853.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAT2	ENST00000460943.6	c.228G>T	p.Arg76Ser	missense_variant, splice_region_variant	Exon 7 of 14	1	NM_032464.3	ENSP00000420494.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.228G>T (p.R76S) alteration is located in exon 7 (coding exon 5) of the LAT2 gene. This alteration results from a G to T substitution at nucleotide position 228, causing the arginine (R) at amino acid position 76 to be replaced by a serine (S). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;D;T;D;D;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	.;.;T;.;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.;L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D
REVEL	Benign	0.098
Sift	Uncertain	0.025	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;.
Vest4		0.53
MutPred		0.30		Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);Gain of relative solvent accessibility (P = 0.0289);.;
MVP		0.15
MPC		0.49
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.47
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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: chr7-73634547;