rs57723738

Positions:

• chr4-56490564-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006947.4(SRP72):​c.1425-4T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000443 in 1,613,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (5 hom.)
• Consequence: SRP72 NM_006947.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01517
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.799

Genes affected

SRP72 (HGNC:11303): (signal recognition particle 72) This gene encodes the 72 kDa subunit of the signal recognition particle (SRP), a ribonucleoprotein complex that mediates the targeting of secretory proteins to the endoplasmic reticulum (ER). The SRP complex consists of a 7S RNA and 6 protein subunits: SRP9, SRP14, SRP19, SRP54, SRP68, and SRP72, that are bound to the 7S RNA as monomers or heterodimers. SRP has at least 3 distinct functions that can be associated with the protein subunits: signal recognition, translational arrest, and ER membrane targeting by interaction with the docking protein. Mutations in this gene are associated with familial bone marrow failure. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-56490564-T-C is Benign according to our data. Variant chr4-56490564-T-C is described in ClinVar as [Benign]. Clinvar id is 436862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 339 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP72	NM_006947.4	c.1425-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642900.1
SRP72	NM_001267722.2	c.1242-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SRP72	XM_024454192.2	c.1425-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SRP72	NR_151856.2	n.1444-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP72	ENST00000642900.1	c.1425-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_006947.4	P1
SRP72	ENST00000510663.6	c.1242-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
SRP72	ENST00000646579.1	n.436-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
SRP72	ENST00000647432.1	n.527-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 337 AN: 152210 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00793

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000617 AC: 154 AN: 249730 Hom.: 3 AF XY: 0.000548 AC XY: 74 AN XY: 134994

Gnomad AFR exome AF: 0.00835

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000257 AC: 375 AN: 1460836 Hom.: 5 Cov.: 30 AF XY: 0.000233 AC XY: 169 AN XY: 726666

Gnomad4 AFR exome AF: 0.00933

Gnomad4 AMR exome AF: 0.000404

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152328 Hom.: 3 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74488

Gnomad4 AFR AF: 0.00796

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 22, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.060
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

Publications

LitVar

Other links and lift over

dbSNP: rs57723738; hg19: chr4-57356730;