chr5-142314028-C-T

Variant names:

• chr5-142314028-C-T
• rs10040443
• NM_001127496.3:c.*181G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001127496.3(SPRY4):​c.*181G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 651,562 control chromosomes in the GnomAD database, including 189,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (38728 hom., cov: 32)
  • Exomes 𝑓: 0.77 (150773 hom.)
• Consequence: SPRY4 NM_001127496.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.871
• 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 17 with or without anosmia

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• hypogonadotropic hypogonadism

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-142314028-C-T is Benign according to our data. Variant chr5-142314028-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127496.3. 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
	SPRY4	NM_001127496.3	MANE Select	c.*181G>A		3_prime_UTR	Exon 2 of 2	NP_001120968.1	Q9C004-1
	SPRY4	NM_030964.5		c.*181G>A		3_prime_UTR	Exon 3 of 3	NP_112226.2
	SPRY4	NM_001293289.3		c.*181G>A		3_prime_UTR	Exon 3 of 3	NP_001280218.1	Q9C004-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRY4	ENST00000434127.3	TSL:1 MANE Select	c.*181G>A		3_prime_UTR	Exon 2 of 2	ENSP00000399468.2	Q9C004-1
	SPRY4	ENST00000344120.4	TSL:1	c.*181G>A		3_prime_UTR	Exon 3 of 3	ENSP00000344967.4	A0A0C4DFS6
	SPRY4	ENST00000889413.1		c.*181G>A		3_prime_UTR	Exon 3 of 3	ENSP00000559472.1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106558 AN: 151956 Hom.: 38700 Cov.: 32

Gnomad AFR AF: 0.496

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.788

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.738

GnomAD4 exome AF: 0.774 AC: 386445 AN: 499488 Hom.: 150773 Cov.: 6 AF XY: 0.775 AC XY: 199701 AN XY: 257764

African (AFR) AF: 0.495 AC: 6723 AN: 13576

American (AMR) AF: 0.815 AC: 15083 AN: 18514

Ashkenazi Jewish (ASJ) AF: 0.813 AC: 11239 AN: 13822

East Asian (EAS) AF: 0.907 AC: 28234 AN: 31126

South Asian (SAS) AF: 0.774 AC: 32402 AN: 41844

European-Finnish (FIN) AF: 0.731 AC: 21414 AN: 29296

Middle Eastern (MID) AF: 0.707 AC: 1522 AN: 2152

European-Non Finnish (NFE) AF: 0.774 AC: 248749 AN: 321552

Other (OTH) AF: 0.764 AC: 21079 AN: 27606

GnomAD4 genome AF: 0.701 AC: 106626 AN: 152074 Hom.: 38728 Cov.: 32 AF XY: 0.704 AC XY: 52324 AN XY: 74302

African (AFR) AF: 0.495 AC: 20534 AN: 41456

American (AMR) AF: 0.787 AC: 12024 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2849 AN: 3472

East Asian (EAS) AF: 0.919 AC: 4753 AN: 5170

South Asian (SAS) AF: 0.788 AC: 3799 AN: 4820

European-Finnish (FIN) AF: 0.739 AC: 7813 AN: 10566

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.771 AC: 52397 AN: 67996

Other (OTH) AF: 0.742 AC: 1565 AN: 2110

Alfa AF: 0.752 Hom.: 161679

Bravo AF: 0.696

Asia WGS AF: 0.797 AC: 2772 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.1
DANN	Benign	0.61
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism (auto)

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: rs10040443; hg19: chr5-141693593;