chr16-3589976-G-A

Variant names:

• chr16-3589976-G-A
• rs3827530
• NM_032444.4:c.3662C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032444.4(SLX4):​c.3662C>T​(p.Ala1221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,613,786 control chromosomes in the GnomAD database, including 3,256 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1221L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.050 (241 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3015 hom.)
• Consequence: SLX4 NM_032444.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.330
• Publications: 25 publications found

Genes affected

SLX4 (HGNC:23845): (SLX4 structure-specific endonuclease subunit) This gene encodes a protein that functions as an assembly component of multiple structure-specific endonucleases. These endonuclease complexes are required for repair of specific types of DNA lesions and critical for cellular responses to replication fork failure. Mutations in this gene were found in patients with Fanconi anemia. [provided by RefSeq, Sep 2016]

SLX4 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group P

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017294586).
• BP6: Variant 16-3589976-G-A is Benign according to our data. Variant chr16-3589976-G-A is described in ClinVar as Benign. ClinVar VariationId is 262048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	NM_032444.4	MANE Select	c.3662C>T	p.Ala1221Val	missense	Exon 12 of 15	NP_115820.2	Q8IY92-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLX4	ENST00000294008.4	TSL:5 MANE Select	c.3662C>T	p.Ala1221Val	missense	Exon 12 of 15	ENSP00000294008.3	Q8IY92-1

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7559 AN: 151906 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.0521

Gnomad FIN AF: 0.0859

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0583 AC: 14614 AN: 250722 AF XY: 0.0579

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0354

Gnomad FIN exome AF: 0.0883

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0503

GnomAD4 exome AF: 0.0614 AC: 89737 AN: 1461762 Hom.: 3015 Cov.: 38 AF XY: 0.0609 AC XY: 44295 AN XY: 727194

African (AFR) AF: 0.00920 AC: 308 AN: 33480

American (AMR) AF: 0.0651 AC: 2912 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 494 AN: 26136

East Asian (EAS) AF: 0.0317 AC: 1257 AN: 39700

South Asian (SAS) AF: 0.0532 AC: 4591 AN: 86258

European-Finnish (FIN) AF: 0.0830 AC: 4421 AN: 53294

Middle Eastern (MID) AF: 0.0276 AC: 159 AN: 5768

European-Non Finnish (NFE) AF: 0.0650 AC: 72256 AN: 1112008

Other (OTH) AF: 0.0553 AC: 3339 AN: 60394

GnomAD4 genome AF: 0.0497 AC: 7556 AN: 152024 Hom.: 241 Cov.: 32 AF XY: 0.0512 AC XY: 3805 AN XY: 74314

African (AFR) AF: 0.0117 AC: 486 AN: 41464

American (AMR) AF: 0.0686 AC: 1048 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.0355 AC: 183 AN: 5158

South Asian (SAS) AF: 0.0530 AC: 254 AN: 4792

European-Finnish (FIN) AF: 0.0859 AC: 909 AN: 10580

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4425 AN: 67972

Other (OTH) AF: 0.0468 AC: 99 AN: 2114

Alfa AF: 0.0572 Hom.: 293

Bravo AF: 0.0464

TwinsUK AF: 0.0612 AC: 227

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.0669 AC: 575

ExAC AF: 0.0583 AC: 7078

Asia WGS AF: 0.0500 AC: 175 AN: 3478

EpiCase AF: 0.0567

EpiControl AF: 0.0583

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group P (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.2
DANN	Benign	0.93
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.33
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.0030
Sift	Benign	0.30	T
Sift4G	Benign	0.34	T
Polyphen		0.019	B
Vest4		0.015
MPC		0.056
ClinPred		0.00066	T
GERP RS		-3.8
Varity_R		0.024
gMVP		0.084
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3827530; hg19: chr16-3639977; COSMIC: COSV53566301;