4-56467644-C-T

Variant names:

• chr4-56467644-C-T
• rs529395062
• NM_006947.4:c.9C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_006947.4(SRP72):​c.9C>T​(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SRP72 NM_006947.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

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]

SRP72 Gene-Disease associations (from GenCC):

• autosomal dominant aplasia and myelodysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ENSG00000289393 (HGNC:58796):

LOC124900706 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 4-56467644-C-T is Benign according to our data. Variant chr4-56467644-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3050359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006947.4. 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
	SRP72	NM_006947.4	MANE Select	c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 19	NP_008878.3
	SRP72	NM_001267722.2		c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 17	NP_001254651.1	O76094-2
	SRP72	NR_151856.2		n.28C>T		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRP72	ENST00000642900.1	MANE Select	c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 19	ENSP00000495128.1	O76094-1
	SRP72	ENST00000510663.6	TSL:1	c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 17	ENSP00000424576.1	O76094-2
	SRP72	ENST00000925431.1		c.9C>T	p.Ser3Ser	synonymous	Exon 1 of 19	ENSP00000595490.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405468 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 697530

African (AFR) AF: 0.00 AC: 0 AN: 29896

American (AMR) AF: 0.00 AC: 0 AN: 35220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24362

East Asian (EAS) AF: 0.00 AC: 0 AN: 34504

South Asian (SAS) AF: 0.00 AC: 0 AN: 80386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085532

Other (OTH) AF: 0.00 AC: 0 AN: 57794

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74390

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	SRP72-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		1.2
PromoterAI		-0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs529395062; hg19: chr4-57333810;