Variant 17-75640811-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001162995.3(SMIM5):c.148C>A(p.Leu50Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,550,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SMIM5
NM_001162995.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.621

Variant links:

Genes affected

SMIM5 (HGNC:40030): (small integral membrane protein 5) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM5 links:

RECQL5 (HGNC:9950): (RecQ like helicase 5) The protein encoded by this gene is a helicase that is important for genome stability. The encoded protein also prevents aberrant homologous recombination by displacing RAD51 from ssDNA. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

RECQL5 links:

SMIM5 (HGNC:):

SMIM5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09091851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMIM5	NM_001162995.3 linkuse as main transcript	c.148C>A	p.Leu50Met	missense_variant	3/3	ENST00000375215.3	NP_001156467.1	Q71RC9
RECQL5	NM_004259.7 linkuse as main transcript	c.1230-9143G>T		intron_variant		ENST00000317905.10	NP_004250.4	O94762-1A0A024R8M9Q8WYH5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SMIM5	ENST00000375215.3 linkuse as main transcript	c.148C>A	p.Leu50Met	missense_variant	3/3	1	NM_001162995.3	ENSP00000364363.3	Q71RC9
RECQL5	ENST00000317905.10 linkuse as main transcript	c.1230-9143G>T		intron_variant		1	NM_004259.7	ENSP00000317636.5	O94762-1
RECQL5	ENST00000423245.6 linkuse as main transcript	c.1149-9143G>T		intron_variant		1		ENSP00000394820.2	O94762-4

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000194

AC:

AN:

154476

Hom.:

AF XY:

0.0000244

AC XY:

AN XY:

82006

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1397962

Hom.:

Cov.:

AF XY:

0.00000580

AC XY:

AN XY:

689526

show subpopulations

Gnomad4 AFR exome

AF:

0.000411

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000717

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000372

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2024

The c.148C>A (p.L50M) alteration is located in exon 3 (coding exon 2) of the SMIM5 gene. This alteration results from a C to A substitution at nucleotide position 148, causing the leucine (L) at amino acid position 50 to be replaced by a methionine (M). 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

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.39

CADD

Benign

5.0

DANN

Uncertain

0.98

DEOGEN2

Benign

0.031

T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.53

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.091

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.11

Sift

Benign

0.048

D;.

Sift4G

Benign

0.070

T;T

Polyphen

0.95

P;P

Vest4

0.30

MutPred

0.30

Loss of catalytic residue at L50 (P = 0.0257);Loss of catalytic residue at L50 (P = 0.0257);

MVP

0.030

ClinPred

0.064

GERP RS

-0.81

Varity_R

0.085

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over