NM_014834.4:c.2335C>T

Variant names:

• chr17-46297468-C-T
• rs1275205266
• NM_014834.4:c.2335C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014834.4(LRRC37A):​c.2335C>T​(p.Arg779Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R779Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 18)
  • Exomes 𝑓: 0.00029 (24 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A NM_014834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.255
• Publications: 0 publications found

Genes affected

LRRC37A (HGNC:29069): (leucine rich repeat containing 37A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARL17B (HGNC:32387): (ADP ribosylation factor like GTPase 17B) Predicted to enable GTP binding activity. Predicted to be involved in intracellular protein transport and vesicle-mediated transport. Predicted to be located in Golgi apparatus. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014755368).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014834.4. 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
	LRRC37A	NM_014834.4	MANE Select	c.2335C>T	p.Arg779Trp	missense	Exon 1 of 14	NP_055649.4	A6NMS7
	ARL17B	NM_001103154.2		c.*21+2058G>A		intron	N/A	NP_001096624.1
	ARL17B	NM_001352769.1		c.*21+2058G>A		intron	N/A	NP_001339698.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC37A	ENST00000320254.5	TSL:1 MANE Select	c.2335C>T	p.Arg779Trp	missense	Exon 1 of 14	ENSP00000326324.5	A6NMS7
	LRRC37A	ENST00000393465.7	TSL:5	c.2335C>T	p.Arg779Trp	missense	Exon 1 of 12	ENSP00000377108.2	A8MUI5
	LRRC37A	ENST00000496930.5	TSL:2	c.-277-2326C>T		intron	N/A	ENSP00000437021.1	E9PP10

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 237 AN: 117498 Hom.: 4 Cov.: 18

Gnomad AFR AF: 0.00648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000773

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: 0.0000536

Gnomad OTH AF: 0.00123

GnomAD2 exomes AF: 0.000753 AC: 38 AN: 50466 AF XY: 0.000983

Gnomad AFR exome AF: 0.00510

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.00220

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000286 AC: 350 AN: 1225214 Hom.: 24 Cov.: 26 AF XY: 0.000240 AC XY: 148 AN XY: 617502

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

African (AFR) AF: 0.00727 AC: 219 AN: 30136

American (AMR) AF: 0.000502 AC: 18 AN: 35860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24490

East Asian (EAS) AF: 0.00 AC: 0 AN: 25204

South Asian (SAS) AF: 0.000375 AC: 30 AN: 79980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46726

Middle Eastern (MID) AF: 0.000803 AC: 3 AN: 3736

European-Non Finnish (NFE) AF: 0.0000377 AC: 35 AN: 927446

Other (OTH) AF: 0.000871 AC: 45 AN: 51636

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00202 AC: 237 AN: 117586 Hom.: 4 Cov.: 18 AF XY: 0.00201 AC XY: 112 AN XY: 55776

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

African (AFR) AF: 0.00646 AC: 224 AN: 34690

American (AMR) AF: 0.000774 AC: 8 AN: 10338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2990

East Asian (EAS) AF: 0.00 AC: 0 AN: 1416

South Asian (SAS) AF: 0.00 AC: 0 AN: 3560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.0000537 AC: 3 AN: 55916

Other (OTH) AF: 0.00122 AC: 2 AN: 1638

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000169 Hom.: 0

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	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.26
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.049
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.11	B
Vest4		0.17
MVP		0.043
ClinPred		0.018	T
GERP RS		-4.1
Varity_R		0.051
gMVP		0.071
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1275205266; hg19: chr17-44374834;