NM_032444.4:c.90C>T

Variant names:

• chr16-3608875-G-A
• rs118089506
• NM_032444.4:c.90C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032444.4(SLX4):​c.90C>T​(p.Ser30Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00833 in 1,614,138 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (66 hom.)
• Consequence: SLX4 NM_032444.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.52
• Publications: 5 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=-0.85).
• BP6: Variant 16-3608875-G-A is Benign according to our data. Variant chr16-3608875-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00619 (943/152252) while in subpopulation AMR AF = 0.0098 (150/15300). AF 95% confidence interval is 0.00885. There are 4 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.90C>T	p.Ser30Ser	synonymous	Exon 2 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.90C>T	p.Ser30Ser	synonymous	Exon 2 of 15	ENSP00000294008.3	Q8IY92-1
	SLX4	ENST00000466154.5	TSL:1	n.385C>T		non_coding_transcript_exon	Exon 1 of 7
	SLX4	ENST00000486524.1	TSL:2	n.718C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00621 AC: 945 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00945

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00604 AC: 1520 AN: 251472 AF XY: 0.00661

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00898

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00855 AC: 12495 AN: 1461886 Hom.: 66 Cov.: 31 AF XY: 0.00871 AC XY: 6335 AN XY: 727244

African (AFR) AF: 0.00134 AC: 45 AN: 33478

American (AMR) AF: 0.00579 AC: 259 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00409 AC: 107 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00718 AC: 619 AN: 86254

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53420

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.00981 AC: 10907 AN: 1112010

Other (OTH) AF: 0.00803 AC: 485 AN: 60396

GnomAD4 genome AF: 0.00619 AC: 943 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74452

African (AFR) AF: 0.00157 AC: 65 AN: 41526

American (AMR) AF: 0.00980 AC: 150 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00747 AC: 36 AN: 4820

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00945 AC: 643 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00755 Hom.: 4

Bravo AF: 0.00641

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group P (4)
-	-	3	not provided (3)
-	-	2	Fanconi anemia (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.55
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

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: rs118089506; hg19: chr16-3658876;