rs7443175

Variant names:

• chr5-142315884-T-C
• rs7443175
• NM_001127496.3:c.-47-729A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030964.5(SPRY4):​c.23-729A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 152,150 control chromosomes in the GnomAD database, including 35,979 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (35973 hom., cov: 33)
  • Exomes 𝑓: 0.77 (6 hom.)
• Consequence: SPRY4 NM_030964.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 6 publications found

Genes affected

SPRY4 (HGNC:15533): (sprouty RTK signaling antagonist 4) This gene encodes a member of a family of cysteine- and proline-rich proteins. The encoded protein is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. Activity of this protein impairs the formation of active GTP-RAS. Nucleotide variation in this gene has been associated with hypogonadotropic hypogonadism 17 with or without anosmia. Alternative splicing results in a multiple transcript variants. [provided by RefSeq, Jun 2014]

SPRY4 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 17 with or without anosmia

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030964.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	NM_001127496.3	MANE Select	c.-47-729A>G		intron	N/A	NP_001120968.1
	SPRY4	NM_030964.5		c.23-729A>G		intron	N/A	NP_112226.2
	SPRY4	NM_001293289.3		c.-47-729A>G		intron	N/A	NP_001280218.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	ENST00000434127.3	TSL:1 MANE Select	c.-47-729A>G		intron	N/A	ENSP00000399468.2
	SPRY4	ENST00000344120.4	TSL:1	c.23-729A>G		intron	N/A	ENSP00000344967.4
	SPRY4	ENST00000889413.1		c.-47-729A>G		intron	N/A	ENSP00000559472.1

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100810 AN: 152010 Hom.: 35952 Cov.: 33

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.810

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.706

GnomAD4 exome AF: 0.773 AC: 17 AN: 22 Hom.: 6 AF XY: 0.800 AC XY: 8 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 6 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.714 AC: 10 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.663 AC: 100849 AN: 152128 Hom.: 35973 Cov.: 33 AF XY: 0.667 AC XY: 49646 AN XY: 74382

African (AFR) AF: 0.376 AC: 15574 AN: 41470

American (AMR) AF: 0.772 AC: 11802 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 2810 AN: 3468

East Asian (EAS) AF: 0.916 AC: 4749 AN: 5182

South Asian (SAS) AF: 0.771 AC: 3726 AN: 4830

European-Finnish (FIN) AF: 0.739 AC: 7822 AN: 10590

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.765 AC: 51983 AN: 67994

Other (OTH) AF: 0.711 AC: 1500 AN: 2110

Alfa AF: 0.737 Hom.: 21581

Bravo AF: 0.653

Asia WGS AF: 0.779 AC: 2709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.9
DANN	Benign	0.63
PhyloP100		0.077
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7443175; hg19: chr5-141695449;