rs73271166

Variant names:

• chr5-148125745-A-G
• rs73271166
• NM_006846.4:c.2762A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006846.4(SPINK5):​c.2762A>G​(p.Asn921Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,614,128 control chromosomes in the GnomAD database, including 99 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (60 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.194
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003077805).
• BP6: Variant 5-148125745-A-G is Benign according to our data. Variant chr5-148125745-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2196/152248) while in subpopulation AFR AF = 0.05 (2077/41514). AF 95% confidence interval is 0.0482. There are 60 homozygotes in GnomAd4. There are 1063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 60 AR gene

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.2762A>G	p.Asn921Ser	missense	Exon 29 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.2852A>G	p.Asn951Ser	missense	Exon 30 of 34	NP_001121170.1	Q9NQ38-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK5	ENST00000256084.8	TSL:1 MANE Select	c.2762A>G	p.Asn921Ser	missense	Exon 29 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.2852A>G	p.Asn951Ser	missense	Exon 30 of 34	ENSP00000352936.3	Q9NQ38-3
	FBXO38-DT	ENST00000667608.1		n.1257-32003T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2188 AN: 152130 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00327 AC: 817 AN: 249532 AF XY: 0.00258

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00133 AC: 1945 AN: 1461880 Hom.: 39 Cov.: 35 AF XY: 0.00116 AC XY: 840 AN XY: 727238

African (AFR) AF: 0.0487 AC: 1629 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1112004

Other (OTH) AF: 0.00247 AC: 149 AN: 60394

GnomAD4 genome AF: 0.0144 AC: 2196 AN: 152248 Hom.: 60 Cov.: 32 AF XY: 0.0143 AC XY: 1063 AN XY: 74456

African (AFR) AF: 0.0500 AC: 2077 AN: 41514

American (AMR) AF: 0.00556 AC: 85 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00525 Hom.: 44

Bravo AF: 0.0160

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0435 AC: 166

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00398 AC: 481

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Netherton syndrome (2)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.63
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.47	N
PhyloP100		0.19
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.071
Sift	Benign	0.69	T
Sift4G	Benign	0.74	T
Polyphen		0.036	B
Vest4		0.099
MVP		0.17
MPC		0.077
ClinPred		0.0023	T
GERP RS		1.8
Varity_R		0.028
gMVP		0.063
Mutation Taster		=99/1	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: rs73271166; hg19: chr5-147505308;