Genetic Variant SMAP1:p.Glu27Gly (chr6-70668103-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001044305.3(SMAP1):c.80A>G(p.Glu27Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E27A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMAP1
NM_001044305.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.45

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32593846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAP1	NM_001044305.3 link	c.80A>G	p.Glu27Gly	missense_variant	Exon 1 of 11	ENST00000370455.8	NP_001037770.1	Q8IYB5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMAP1	ENST00000370455.8 link	c.80A>G	p.Glu27Gly	missense_variant	Exon 1 of 11	1	NM_001044305.3	ENSP00000359484.3	Q8IYB5-1
SMAP1	ENST00000316999.9 link	c.80A>G	p.Glu27Gly	missense_variant	Exon 1 of 10	1		ENSP00000313382.5	Q8IYB5-2
SMAP1	ENST00000370452.7 link	c.80A>G	p.Glu27Gly	missense_variant	Exon 1 of 11	2		ENSP00000359481.3	Q8IYB5-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1451484

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722060

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31660

American (AMR)

AF:

0.00

AC:

AN:

43990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

38502

South Asian (SAS)

AF:

0.00

AC:

AN:

84896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1107852

Other (OTH)

AF:

0.00

AC:

AN:

59968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;.;T

Eigen

Benign

0.051

Eigen_PC

Benign

0.065

FATHMM_MKL

Benign

0.67

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

5.4

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.0020

B;B;D

Vest4

0.46

MutPred

0.42

Loss of methylation at K31 (P = 0.0427);Loss of methylation at K31 (P = 0.0427);Loss of methylation at K31 (P = 0.0427);

MVP

0.48

MPC

2.4

ClinPred

0.99

GERP RS

2.2

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.73

gMVP

0.79

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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6-70668103-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over