chr17-46297456-C-T

Variant names:

• chr17-46297456-C-T
• rs1367405331
• NM_014834.4:c.2323C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014834.4(LRRC37A):​c.2323C>T​(p.Pro775Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0000087 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRRC37A NM_014834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.549
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07340926).

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.2323C>T	p.Pro775Ser	missense	Exon 1 of 14	NP_055649.4	A6NMS7
	ARL17B	NM_001103154.2		c.*21+2070G>A		intron	N/A	NP_001096624.1
	ARL17B	NM_001352769.1		c.*21+2070G>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.2323C>T	p.Pro775Ser	missense	Exon 1 of 14	ENSP00000326324.5	A6NMS7
	LRRC37A	ENST00000393465.7	TSL:5	c.2323C>T	p.Pro775Ser	missense	Exon 1 of 12	ENSP00000377108.2	A8MUI5
	LRRC37A	ENST00000496930.5	TSL:2	c.-277-2338C>T		intron	N/A	ENSP00000437021.1	E9PP10

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 5 AN: 125342 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000136

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: 0.00

GnomAD2 exomes AF: 0.0000908 AC: 5 AN: 55068 AF XY: 0.000144

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000868 AC: 11 AN: 1266728 Hom.: 1 Cov.: 29 AF XY: 0.00000628 AC XY: 4 AN XY: 636558

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

African (AFR) AF: 0.000226 AC: 7 AN: 31034

American (AMR) AF: 0.0000549 AC: 2 AN: 36440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24730

East Asian (EAS) AF: 0.00 AC: 0 AN: 24894

South Asian (SAS) AF: 0.00 AC: 0 AN: 80920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3894

European-Non Finnish (NFE) AF: 0.00000207 AC: 2 AN: 965100

Other (OTH) AF: 0.00 AC: 0 AN: 53132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000117132), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000399 AC: 5 AN: 125342 Hom.: 0 Cov.: 18 AF XY: 0.0000502 AC XY: 3 AN XY: 59710

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

African (AFR) AF: 0.000136 AC: 5 AN: 36682

American (AMR) AF: 0.00 AC: 0 AN: 11264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3116

East Asian (EAS) AF: 0.00 AC: 0 AN: 1836

South Asian (SAS) AF: 0.00 AC: 0 AN: 3830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58954

Other (OTH) AF: 0.00 AC: 0 AN: 1746

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0672034), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 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	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.14
DANN	Benign	0.71
DEOGEN2	Benign	0.076	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.55
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.039
Sift	Benign	0.077	T
Sift4G	Benign	0.28	T
Polyphen		0.0070	B
Vest4		0.070
MutPred		0.20		Gain of MoRF binding (P = 0.0511)
MVP		0.068
ClinPred		0.038	T
GERP RS		-4.0
Varity_R		0.060
gMVP		0.10

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: rs1367405331; hg19: chr17-44374822;