16-3606481-C-T

Variant names:

• chr16-3606481-C-T
• rs8061528
• NM_032444.4:c.753G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032444.4(SLX4):​c.753G>A​(p.Ala251Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,613,518 control chromosomes in the GnomAD database, including 36,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A251A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (3787 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32486 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.42
• Publications: 45 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-3606481-C-T is Benign according to our data. Variant chr16-3606481-C-T is described in ClinVar as Benign. ClinVar VariationId is 262058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 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.753G>A	p.Ala251Ala	synonymous	Exon 3 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.753G>A	p.Ala251Ala	synonymous	Exon 3 of 15	ENSP00000294008.3	Q8IY92-1
	SLX4	ENST00000466154.5	TSL:1	n.1048G>A		non_coding_transcript_exon	Exon 2 of 7
	SLX4	ENST00000486524.1	TSL:2	n.1381G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33379 AN: 152028 Hom.: 3771 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.212 AC: 53110 AN: 249970 AF XY: 0.213

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.301

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.209 AC: 305007 AN: 1461372 Hom.: 32486 Cov.: 33 AF XY: 0.209 AC XY: 151921 AN XY: 727010

African (AFR) AF: 0.242 AC: 8105 AN: 33466

American (AMR) AF: 0.199 AC: 8880 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 5614 AN: 26130

East Asian (EAS) AF: 0.330 AC: 13107 AN: 39698

South Asian (SAS) AF: 0.221 AC: 19082 AN: 86246

European-Finnish (FIN) AF: 0.169 AC: 9022 AN: 53416

Middle Eastern (MID) AF: 0.223 AC: 1286 AN: 5764

European-Non Finnish (NFE) AF: 0.204 AC: 226976 AN: 1111560

Other (OTH) AF: 0.214 AC: 12935 AN: 60372

GnomAD4 genome AF: 0.220 AC: 33433 AN: 152146 Hom.: 3787 Cov.: 32 AF XY: 0.218 AC XY: 16215 AN XY: 74386

African (AFR) AF: 0.254 AC: 10540 AN: 41478

American (AMR) AF: 0.200 AC: 3059 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 741 AN: 3472

East Asian (EAS) AF: 0.306 AC: 1583 AN: 5174

South Asian (SAS) AF: 0.217 AC: 1048 AN: 4820

European-Finnish (FIN) AF: 0.166 AC: 1757 AN: 10598

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13955 AN: 68000

Other (OTH) AF: 0.231 AC: 487 AN: 2108

Alfa AF: 0.202 Hom.: 5006

Bravo AF: 0.222

Asia WGS AF: 0.273 AC: 948 AN: 3478

EpiCase AF: 0.211

EpiControl AF: 0.206

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group P (5)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.54
DANN	Benign	0.70
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs8061528; hg19: chr16-3656482; COSMIC: COSV53567315;