Genetic Variant SMAP1:p.Pro184Leu (chr6-70798712-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001044305.3(SMAP1):c.551C>T(p.Pro184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,558,584 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 6 hom. )

Consequence

SMAP1
NM_001044305.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

3 publications found

Variant links:

Genes affected

SMAP1 (HGNC:19651): (small ArfGAP 1) The protein encoded by this gene is similar to the mouse stromal membrane-associated protein-1. This similarity suggests that this human gene product is also a type II membrane glycoprotein involved in the erythropoietic stimulatory activity of stromal cells. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

SMAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005534649).

BS2

High AC in GnomAd4 at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAP1	NM_001044305.3 link	c.551C>T	p.Pro184Leu	missense_variant	Exon 6 of 11	ENST00000370455.8	NP_001037770.1	Q8IYB5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAP1	ENST00000370455.8 link	c.551C>T	p.Pro184Leu	missense_variant	Exon 6 of 11	1	NM_001044305.3	ENSP00000359484.3		Q8IYB5-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

151340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000970

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.000966

GnomAD2 exomes

AF:

0.00113

AC:

226

AN:

200204

AF XY:

0.00126

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000417

Gnomad FIN exome

AF:

0.000669

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00158

GnomAD4 exome

AF:

0.00188

AC:

2644

AN:

1407138

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1281

AN XY:

697406

show subpopulations

African (AFR)

AF:

0.000356

AC:

AN:

30876

American (AMR)

AF:

0.00126

AC:

AN:

38916

Ashkenazi Jewish (ASJ)

AF:

0.0000402

AC:

AN:

24848

East Asian (EAS)

AF:

0.000106

AC:

AN:

37886

South Asian (SAS)

AF:

0.0000661

AC:

AN:

75636

European-Finnish (FIN)

AF:

0.000829

AC:

AN:

50654

Middle Eastern (MID)

AF:

0.000357

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00224

AC:

2434

AN:

1084950

Other (OTH)

AF:

0.00166

AC:

AN:

57774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

151446

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

73988

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41382

American (AMR)

AF:

0.00171

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000580

AC:

AN:

5168

South Asian (SAS)

AF:

0.000209

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.000970

AC:

AN:

10304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00229

AC:

155

AN:

67800

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00117

AC:

ExAC

AF:

0.000929

AC:

112

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.551C>T (p.P184L) alteration is located in exon 6 (coding exon 6) of the SMAP1 gene. This alteration results from a C to T substitution at nucleotide position 551, causing the proline (P) at amino acid position 184 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.027

.;.;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.0021

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.58

T;T;T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.0055

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;.;L;.

PhyloP100

1.8

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

D;D;D;.

REVEL

Benign

0.028

Sift

Uncertain

0.021

D;D;T;.

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.0030

B;B;B;.

Vest4

0.18

MVP

0.14

MPC

0.13

ClinPred

0.019

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.076

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(source)

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

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6-70798712-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over