Genetic Variant SPRYD4:p.Glu36Lys (chr12-56469059-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_207344.4(SPRYD4):c.106G>A(p.Glu36Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,420,426 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 1 hom. )

Consequence

SPRYD4
NM_207344.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.17

Variant links:

Genes affected

SPRYD4 (HGNC:27468): (SPRY domain containing 4) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SPRYD4 links:

MIP (HGNC:7103): (major intrinsic protein of lens fiber) Major intrinsic protein is a member of the water-transporting aquaporins as well as the original member of the MIP family of channel proteins. The function of the fiber cell membrane protein encoded by this gene is undetermined, yet this protein is speculated to play a role in intracellular communication. The MIP protein is expressed in the ocular lens and is required for correct lens function. This gene has been mapped among aquaporins AQP2, AQP5, and AQP6, in a potential gene cluster at 12q13. [provided by RefSeq, Jul 2008]

MIP links:

ENSG00000285528 (HGNC:):

ENSG00000285528 links:

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ACMG classification

Classification made for transcript

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
SPRYD4	NM_207344.4 link	c.106G>A	p.Glu36Lys	missense_variant	Exon 2 of 2	ENST00000338146.7	NP_997227.1	Q8WW59

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRYD4	ENST00000338146.7 link	c.106G>A	p.Glu36Lys	missense_variant	Exon 2 of 2	1	NM_207344.4	ENSP00000338034.5		Q8WW59
ENSG00000285528	ENST00000648304.1 link	n.183-15304C>T		intron_variant	Intron 1 of 3			ENSP00000497190.1		A0A3B3IS89

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000135

AC:

AN:

222030

Hom.:

AF XY:

0.00000833

AC XY:

AN XY:

120108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000776

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000106

AC:

AN:

1420426

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

702914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000110

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000458

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.106G>A (p.E36K) alteration is located in exon 2 (coding exon 2) of the SPRYD4 gene. This alteration results from a G to A substitution at nucleotide position 106, causing the glutamic acid (E) at amino acid position 36 to be replaced by a lysine (K). 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

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Benign

0.062

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.81

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.78

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.84

REVEL

Benign

0.29

Sift

Benign

0.17

Sift4G

Benign

0.71

Vest4

0.69

MutPred

0.53

Gain of MoRF binding (P = 0.012);

MVP

0.50

MPC

0.99

ClinPred

0.86

GERP RS

4.7

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over