NM_144648.3:c.749C>T

Variant names:

• chr7-134158113-C-T
• rs779675347
• NM_144648.3:c.749C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_144648.3(LRGUK):​c.749C>T​(p.Thr250Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LRGUK NM_144648.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.59
• Publications: 6 publications found

Genes affected

LRGUK (HGNC:21964): (leucine rich repeats and guanylate kinase domain containing) Predicted to enable guanylate kinase activity. Predicted to be involved in axoneme assembly and spermatogenesis. Predicted to be located in acrosomal vesicle and manchette. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-134158113-C-T is Benign according to our data. Variant chr7-134158113-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3291286.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144648.3. 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
	LRGUK	NM_144648.3	MANE Select	c.749C>T	p.Thr250Met	missense	Exon 6 of 20	NP_653249.1	Q96M69
	LRGUK	NM_001365700.3		c.749C>T	p.Thr250Met	missense	Exon 6 of 16	NP_001352629.1	A0A8Q3SI13
	LRGUK	NM_001365701.3		c.749C>T	p.Thr250Met	missense	Exon 6 of 16	NP_001352630.1	A0A2R8YEJ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRGUK	ENST00000285928.3	TSL:1 MANE Select	c.749C>T	p.Thr250Met	missense	Exon 6 of 20	ENSP00000285928.2	Q96M69
	LRGUK	ENST00000695542.2		c.749C>T	p.Thr250Met	missense	Exon 6 of 16	ENSP00000511999.1	A0A8Q3SI13
	LRGUK	ENST00000645682.1		c.749C>T	p.Thr250Met	missense	Exon 6 of 16	ENSP00000495637.1	A0A2R8YEJ5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250862 AF XY: 0.0000369

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460592 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726578

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86104

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111190

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.091
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.87
DANN	Benign	0.71
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.056
Sift	Benign	0.13	T
Sift4G	Benign	0.076	T
Polyphen		0.058	B
Vest4		0.14
MutPred		0.28		Loss of ubiquitination at K248 (P = 0.2258)
MVP		0.10
MPC		0.051
ClinPred		0.037	T
GERP RS		-2.2
Varity_R		0.016
gMVP		0.22
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 46

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

Other links and lift over

dbSNP: rs779675347; hg19: chr7-133842866; COSMIC: COSV53635773;