NM_006846.4:c.1344G>A

Variant names:

• chr5-148101822-G-A
• rs17107741
• NM_006846.4:c.1344G>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_006846.4(SPINK5):​c.1344G>A​(p.Arg448Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,613,694 control chromosomes in the GnomAD database, including 1,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (642 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (552 hom.)
• Consequence: SPINK5 NM_006846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.30
• Publications: 1 publications found

Genes affected

SPINK5 (HGNC:15464): (serine peptidase inhibitor Kazal type 5) This gene encodes a multidomain serine protease inhibitor that contains 15 potential inhibitory domains. The encoded preproprotein is proteolytically processed to generate multiple protein products, which may exhibit unique activities and specificities. These proteins may play a role in skin and hair morphogenesis, as well as anti-inflammatory and antimicrobial protection of mucous epithelia. Mutations in this gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. This gene is present in a gene cluster on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

FBXO38-DT (HGNC:55589): (FBXO38 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-148101822-G-A is Benign according to our data. Variant chr5-148101822-G-A is described in ClinVar as Benign. ClinVar VariationId is 260045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006846.4. 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
	SPINK5	NM_006846.4	MANE Select	c.1344G>A	p.Arg448Arg	synonymous	Exon 15 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1344G>A	p.Arg448Arg	synonymous	Exon 15 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1344G>A	p.Arg448Arg	synonymous	Exon 15 of 28	NP_001121171.1	Q9NQ38-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.1344G>A	p.Arg448Arg	synonymous	Exon 15 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1344G>A	p.Arg448Arg	synonymous	Exon 15 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1344G>A	p.Arg448Arg	synonymous	Exon 15 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7573 AN: 152020 Hom.: 643 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0129 AC: 3204 AN: 249028 AF XY: 0.0101

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.00884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.00678

GnomAD4 exome AF: 0.00514 AC: 7518 AN: 1461556 Hom.: 552 Cov.: 31 AF XY: 0.00440 AC XY: 3202 AN XY: 727084

African (AFR) AF: 0.177 AC: 5912 AN: 33450

American (AMR) AF: 0.0106 AC: 472 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00937 AC: 54 AN: 5764

European-Non Finnish (NFE) AF: 0.000297 AC: 330 AN: 1111766

Other (OTH) AF: 0.0119 AC: 716 AN: 60384

GnomAD4 genome AF: 0.0499 AC: 7585 AN: 152138 Hom.: 642 Cov.: 32 AF XY: 0.0485 AC XY: 3608 AN XY: 74374

African (AFR) AF: 0.173 AC: 7173 AN: 41456

American (AMR) AF: 0.0195 AC: 298 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68014

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0146 Hom.: 172

Bravo AF: 0.0579

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	Netherton syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.063
DANN	Benign	0.43
PhyloP100		-2.3
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: rs17107741; hg19: chr5-147481385;