4-56467655-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006947.4(SRP72):c.20G>C(p.Gly7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,561,500 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G7E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0073 (20 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (12 hom.)
• Consequence: SRP72 NM_006947.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.24

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066815317).
• BP6: Variant 4-56467655-G-C is Benign according to our data. Variant chr4-56467655-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 377137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0073 (1111/152254) while in subpopulation AFR AF= 0.0255 (1059/41550). AF 95% confidence interval is 0.0242. There are 20 homozygotes in gnomad4. There are 515 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRP72	NM_006947.4	c.20G>C	p.Gly7Ala	missense_variant	1/19	ENST00000642900.1
SRP72	NM_001267722.2	c.20G>C	p.Gly7Ala	missense_variant	1/17
SRP72	XM_024454192.2	c.20G>C	p.Gly7Ala	missense_variant	1/17
SRP72	NR_151856.2	n.39G>C		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRP72	ENST00000642900.1	c.20G>C	p.Gly7Ala	missense_variant	1/19		NM_006947.4	P1
SRP72	ENST00000510663.6	c.20G>C	p.Gly7Ala	missense_variant	1/17	1
SRP72	ENST00000504757.2	c.20G>C	p.Gly7Ala	missense_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1109 AN: 152136 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00163 AC: 326 AN: 199632 Hom.: 5 AF XY: 0.00119 AC XY: 132 AN XY: 110750

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000731 AC: 1030 AN: 1409246 Hom.: 12 Cov.: 30 AF XY: 0.000650 AC XY: 455 AN XY: 699876

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00209

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000290

Gnomad4 SAS exome AF: 0.000173

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000975

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00730 AC: 1111 AN: 152254 Hom.: 20 Cov.: 31 AF XY: 0.00692 AC XY: 515 AN XY: 74440

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000468 Hom.: 0

Bravo AF: 0.00873

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0173 AC: 76

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00216 AC: 262

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SRP72 p.Gly7Ala variant was not identified in the literature or in the Cosmic database but was identified in dbSNP (ID: rs139502866), ClinVar (reported benign and likely benign) and LOVD 3.0. The variant was identified in control databases in 547 of 230982 chromosomes (8 homozygous) at a frequency of 0.002368 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 481 of 19916 chromosomes (freq: 0.02415), Latino in 46 of 25576 chromosomes (freq: 0.001799), Other in 6 of 5494 chromosomes (freq: 0.001092), South Asian in 3 of 25530 chromosomes (freq: 0.000118), European (non-Finnish) in 11 of 108258 chromosomes (freq: 0.000102), but was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Gly7 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 09, 2017

- -

Autosomal dominant aplasia and myelodysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.73	T;T;.;T
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L;L;L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.59	N;N;.;.
REVEL	Benign	0.27
Sift	Benign	0.31	T;T;.;.
Sift4G	Benign	0.55	T;T;.;T
Polyphen		0.060	B;.;B;.
Vest4		0.070
MVP		0.77
MPC		0.32
ClinPred		0.048	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.050
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs139502866; hg19: chr4-57333821;