1-153040235-A-G

Variant names:

• chr1-153040235-A-G
• rs41290408
• NM_006945.5:c.112T>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006945.5(SPRR2D):​c.112T>C​(p.Ser38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,612,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SPRR2D NM_006945.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.51

Genes affected

SPRR2D (HGNC:11264): (small proline rich protein 2D) Predicted to be involved in keratinization. Predicted to act upstream of or within female gonad development and response to estradiol. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008077502).
• BP6: Variant 1-153040235-A-G is Benign according to our data. Variant chr1-153040235-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2320734.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRR2D	NM_006945.5	c.112T>C	p.Ser38Pro	missense_variant	Exon 2 of 2	ENST00000360379.4	NP_008876.3
SPRR2D	NM_001382248.1	c.112T>C	p.Ser38Pro	missense_variant	Exon 2 of 2		NP_001369177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRR2D	ENST00000360379.4	c.112T>C	p.Ser38Pro	missense_variant	Exon 2 of 2	1	NM_006945.5	ENSP00000353542.3
SPRR2D	ENST00000368756.1	c.112T>C	p.Ser38Pro	missense_variant	Exon 3 of 3	2		ENSP00000357745.1
SPRR2D	ENST00000368757.1	c.112T>C	p.Ser38Pro	missense_variant	Exon 2 of 2	3		ENSP00000357746.1
SPRR2D	ENST00000368758.3	c.112T>C	p.Ser38Pro	missense_variant	Exon 2 of 2	2		ENSP00000357747.3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000486 AC: 122 AN: 251042 Hom.: 0 AF XY: 0.000450 AC XY: 61 AN XY: 135670

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000351 AC: 512 AN: 1460336 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 254 AN XY: 726496

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74384

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000574 Hom.: 0

Bravo AF: 0.000484

ExAC AF: 0.000544 AC: 66

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 16, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.8
DANN	Benign	0.42
DEOGEN2	Benign	0.0020	T;T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.00044	N
LIST_S2	Benign	0.20	.;.;.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0081	T;T;T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	1.8	N;N;N;N
REVEL	Benign	0.068
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.15
MVP		0.10
MPC		0.60
ClinPred		0.0032	T
GERP RS		0.16
Varity_R		0.14
gMVP		0.0012

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: rs41290408; hg19: chr1-153012711; COSMIC: COSV64209122;