1-41017784-C-T

Position:

• chr1-41017784-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144990.4(SLFNL1):​c.808G>A​(p.Gly270Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,453,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SLFNL1 NM_144990.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

Genes affected

SLFNL1 (HGNC:26313): (schlafen like 1) Predicted to enable ATP binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SLFNL1-AS1 (HGNC:44126): (SLFNL1 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLFNL1	NM_144990.4	c.808G>A	p.Gly270Ser	missense_variant	4/6	ENST00000302946.13	NP_659427.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLFNL1	ENST00000302946.13	c.808G>A	p.Gly270Ser	missense_variant	4/6	1	NM_144990.4	ENSP00000304401.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1453820 Hom.: 0 Cov.: 31 AF XY: 0.00000693 AC XY: 5 AN XY: 721978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000904

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.808G>A (p.G270S) alteration is located in exon 4 (coding exon 2) of the SLFNL1 gene. This alteration results from a G to A substitution at nucleotide position 808, causing the glycine (G) at amino acid position 270 to be replaced by a serine (S). 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	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;T;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	.;T;D;D;.
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Pathogenic	3.1	M;M;M;.;M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.48
Sift	Benign	0.050	D;D;D;T;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.91
MutPred		0.77		Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);Gain of disorder (P = 0.0711);.;Gain of disorder (P = 0.0711);
MVP		0.51
MPC		0.34
ClinPred		0.94	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs957135235; hg19: chr1-41483456;