chr17-41140118-A-T

Variant names:

• chr17-41140118-A-T
• rs750466229
• NM_030976.2:c.370T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_030976.2(KRTAP4-6):​c.370T>A​(p.Cys124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,453,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 39)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: KRTAP4-6 NM_030976.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

Genes affected

KRTAP4-6 (HGNC:18909): (keratin associated protein 4-6) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1597389).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030976.2. 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
	KRTAP4-6	NM_030976.2	MANE Select	c.370T>A	p.Cys124Ser	missense	Exon 1 of 1	NP_112238.1	Q9BYQ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-6	ENST00000345847.5	TSL:6 MANE Select	c.370T>A	p.Cys124Ser	missense	Exon 1 of 1	ENSP00000328270.5	Q9BYQ5

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152092 Hom.: 0 Cov.: 39

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 37 AN: 249400 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000103 AC: 134 AN: 1301518 Hom.: 0 Cov.: 199 AF XY: 0.000116 AC XY: 75 AN XY: 645664

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28450

American (AMR) AF: 0.000316 AC: 11 AN: 34822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21924

East Asian (EAS) AF: 0.00 AC: 0 AN: 33648

South Asian (SAS) AF: 0.000148 AC: 11 AN: 74202

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46896

Middle Eastern (MID) AF: 0.00259 AC: 13 AN: 5014

European-Non Finnish (NFE) AF: 0.0000886 AC: 89 AN: 1004402

Other (OTH) AF: 0.000173 AC: 9 AN: 52160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152208 Hom.: 0 Cov.: 39 AF XY: 0.0000537 AC XY: 4 AN XY: 74424

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000436673), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000166 Hom.: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.4
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.10
Sift	Benign	0.053	T
Sift4G	Benign	0.065	T
Vest4		0.16
MutPred		0.44		Loss of stability (P = 0.0238)
MVP		0.14
MPC		0.065
ClinPred		0.12	T
GERP RS		1.6
PromoterAI		-0.0042	Neutral
Varity_R		0.22
gMVP		0.23
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs750466229; hg19: chr17-39296370;