rs28516461

Variant names:

• chr16-3606556-G-A
• rs28516461
• NM_032444.4:c.678C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3606556-G-A
• chr16-3606556-G-T

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.678C>T​(p.His226His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 1,614,068 control chromosomes in the GnomAD database, including 3,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1447 hom., cov: 32)
  • Exomes 𝑓: 0.030 (2430 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.120
• Publications: 11 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=-0.87).
• BP6: Variant 16-3606556-G-A is Benign according to our data. Variant chr16-3606556-G-A is described in ClinVar as Benign. ClinVar VariationId is 262057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.249 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.678C>T	p.His226His	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.678C>T	p.His226His	synonymous	Exon 3 of 15	ENSP00000294008.3	Q8IY92-1
	SLX4	ENST00000466154.5	TSL:1	n.973C>T		non_coding_transcript_exon	Exon 2 of 7
	SLX4	ENST00000486524.1	TSL:2	n.1306C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13520 AN: 152064 Hom.: 1444 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0843

GnomAD2 exomes AF: 0.0492 AC: 12359 AN: 251426 AF XY: 0.0493

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0314

Gnomad EAS exome AF: 0.0512

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0300 AC: 43897 AN: 1461888 Hom.: 2430 Cov.: 33 AF XY: 0.0321 AC XY: 23323 AN XY: 727244

African (AFR) AF: 0.276 AC: 9237 AN: 33480

American (AMR) AF: 0.0289 AC: 1292 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 821 AN: 26136

East Asian (EAS) AF: 0.0482 AC: 1912 AN: 39700

South Asian (SAS) AF: 0.123 AC: 10588 AN: 86258

European-Finnish (FIN) AF: 0.0133 AC: 711 AN: 53420

Middle Eastern (MID) AF: 0.0697 AC: 402 AN: 5768

European-Non Finnish (NFE) AF: 0.0145 AC: 16173 AN: 1112006

Other (OTH) AF: 0.0457 AC: 2761 AN: 60396

GnomAD4 genome AF: 0.0890 AC: 13537 AN: 152180 Hom.: 1447 Cov.: 32 AF XY: 0.0890 AC XY: 6625 AN XY: 74406

African (AFR) AF: 0.253 AC: 10481 AN: 41470

American (AMR) AF: 0.0524 AC: 801 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3466

East Asian (EAS) AF: 0.0460 AC: 238 AN: 5176

South Asian (SAS) AF: 0.125 AC: 602 AN: 4824

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0136 AC: 925 AN: 68030

Other (OTH) AF: 0.0834 AC: 176 AN: 2110

Alfa AF: 0.0448 Hom.: 1180

Bravo AF: 0.0993

Asia WGS AF: 0.105 AC: 363 AN: 3478

EpiCase AF: 0.0181

EpiControl AF: 0.0191

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.98
DANN	Benign	0.89
PhyloP100		-0.12
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: rs28516461; hg19: chr16-3656557; COSMIC: COSV53564444;