7-74221678-C-T

Variant names:

• chr7-74221678-C-T
• rs782169191
• NM_032464.3:c.374C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032464.3(LAT2):​c.374C>T​(p.Ser125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,738 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LAT2 NM_032464.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.602
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03231561).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032464.3. 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
	LAT2	NM_032464.3	MANE Select	c.374C>T	p.Ser125Leu	missense	Exon 10 of 14	NP_115853.2	Q9GZY6-1
	LAT2	NM_014146.4		c.374C>T	p.Ser125Leu	missense	Exon 9 of 13	NP_054865.2
	LAT2	NM_032463.3		c.374C>T	p.Ser125Leu	missense	Exon 10 of 14	NP_115852.1	Q9GZY6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAT2	ENST00000460943.6	TSL:1 MANE Select	c.374C>T	p.Ser125Leu	missense	Exon 10 of 14	ENSP00000420494.1	Q9GZY6-1
	LAT2	ENST00000275635.11	TSL:1	c.374C>T	p.Ser125Leu	missense	Exon 10 of 14	ENSP00000275635.7	Q9GZY6-1
	LAT2	ENST00000344995.9	TSL:1	c.374C>T	p.Ser125Leu	missense	Exon 9 of 13	ENSP00000344881.5	Q9GZY6-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151904 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.000482

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248412 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460834 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726726

African (AFR) AF: 0.0000299 AC: 1 AN: 33436

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111440

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151904 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74188

African (AFR) AF: 0.00 AC: 0 AN: 41262

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000482 AC: 1 AN: 2076

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.7
DANN	Benign	0.28
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.60
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.030
Sift	Benign	0.72	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.24		Loss of disorder (P = 0.0334)
MVP		0.061
MPC		0.078
ClinPred		0.0077	T
GERP RS		-2.2
Varity_R		0.032
gMVP		0.037
Mutation Taster		=99/1	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: rs782169191; hg19: chr7-73636008; COSMIC: COSV51922678; COSMIC: COSV51922678;