5-148097988-C-T

Variant names:

• chr5-148097988-C-T
• rs34482796
• NM_006846.4:c.1004C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006846.4(SPINK5):​c.1004C>T​(p.Ala335Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,609,704 control chromosomes in the GnomAD database, including 209,662 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16898 hom., cov: 32)
  • Exomes 𝑓: 0.51 (192764 hom.)
• Consequence: SPINK5 NM_006846.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.365
• Publications: 32 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=7.637391E-6).
• BP6: Variant 5-148097988-C-T is Benign according to our data. Variant chr5-148097988-C-T is described in ClinVar as Benign. ClinVar VariationId is 139257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.579 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.1004C>T	p.Ala335Val	missense	Exon 11 of 33	NP_006837.2	Q9NQ38-1
	SPINK5	NM_001127698.2		c.1004C>T	p.Ala335Val	missense	Exon 11 of 34	NP_001121170.1	Q9NQ38-3
	SPINK5	NM_001127699.2		c.1004C>T	p.Ala335Val	missense	Exon 11 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.1004C>T	p.Ala335Val	missense	Exon 11 of 33	ENSP00000256084.7	Q9NQ38-1
	SPINK5	ENST00000359874.7	TSL:1	c.1004C>T	p.Ala335Val	missense	Exon 11 of 34	ENSP00000352936.3	Q9NQ38-3
	SPINK5	ENST00000398454.5	TSL:1	c.1004C>T	p.Ala335Val	missense	Exon 11 of 28	ENSP00000381472.1	Q9NQ38-2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69799 AN: 151700 Hom.: 16891 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.487

GnomAD2 exomes AF: 0.520 AC: 129193 AN: 248480 AF XY: 0.517

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.510 AC: 744243 AN: 1457884 Hom.: 192764 Cov.: 36 AF XY: 0.509 AC XY: 369397 AN XY: 725432

African (AFR) AF: 0.284 AC: 9464 AN: 33332

American (AMR) AF: 0.686 AC: 30587 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11882 AN: 26028

East Asian (EAS) AF: 0.450 AC: 17801 AN: 39566

South Asian (SAS) AF: 0.486 AC: 41891 AN: 86160

European-Finnish (FIN) AF: 0.545 AC: 29029 AN: 53288

Middle Eastern (MID) AF: 0.511 AC: 2934 AN: 5738

European-Non Finnish (NFE) AF: 0.514 AC: 570437 AN: 1109012

Other (OTH) AF: 0.502 AC: 30218 AN: 60200

GnomAD4 genome AF: 0.460 AC: 69821 AN: 151820 Hom.: 16898 Cov.: 32 AF XY: 0.464 AC XY: 34418 AN XY: 74196

African (AFR) AF: 0.292 AC: 12111 AN: 41408

American (AMR) AF: 0.589 AC: 8974 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3468

East Asian (EAS) AF: 0.475 AC: 2441 AN: 5138

South Asian (SAS) AF: 0.492 AC: 2371 AN: 4822

European-Finnish (FIN) AF: 0.533 AC: 5626 AN: 10546

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.517 AC: 35106 AN: 67890

Other (OTH) AF: 0.487 AC: 1029 AN: 2112

Alfa AF: 0.498 Hom.: 58548

Bravo AF: 0.461

TwinsUK AF: 0.526 AC: 1950

ALSPAC AF: 0.521 AC: 2009

ESP6500AA AF: 0.298 AC: 1107

ESP6500EA AF: 0.506 AC: 4153

ExAC AF: 0.507 AC: 61174

Asia WGS AF: 0.519 AC: 1800 AN: 3478

EpiCase AF: 0.513

EpiControl AF: 0.524

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Netherton syndrome (2)
-	-	1	Ichthyosis linearis circumflexa (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.025	T
MetaRNN	Benign	0.0000076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.36
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.037
Sift	Benign	0.23	T
Sift4G	Benign	0.16	T
Polyphen		0.017	B
Vest4		0.14
MPC		0.11
ClinPred		0.014	T
GERP RS		2.6
Varity_R		0.12
gMVP		0.64
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34482796; hg19: chr5-147477551; COSMIC: COSV56260859; COSMIC: COSV56260859;