chr11-71527716-C-G

Variant names:

• chr11-71527716-C-G
• rs765423098
• NM_001012503.2:c.416C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001012503.2(KRTAP5-7):​c.416C>G​(p.Ser139Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,199,220 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP5-7 NM_001012503.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.19
• Publications: 1 publications found

Genes affected

KRTAP5-7 (HGNC:23602): (keratin associated protein 5-7) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038061857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP5-7	NM_001012503.2	c.416C>G	p.Ser139Cys	missense_variant	Exon 1 of 1	ENST00000398536.6	NP_001012521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP5-7	ENST00000398536.6	c.416C>G	p.Ser139Cys	missense_variant	Exon 1 of 1	6	NM_001012503.2	ENSP00000417330.2

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 38 AN: 137082 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000725

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.000494

Gnomad FIN AF: 0.000209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000172

Gnomad OTH AF: 0.00109

GnomAD4 exome AF: 0.0000233 AC: 28 AN: 1199220 Hom.: 0 Cov.: 35 AF XY: 0.0000183 AC XY: 11 AN XY: 600338

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

African (AFR) AF: 0.000423 AC: 12 AN: 28338

American (AMR) AF: 0.0000232 AC: 1 AN: 43062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24204

East Asian (EAS) AF: 0.00 AC: 0 AN: 37962

South Asian (SAS) AF: 0.00 AC: 0 AN: 79370

European-Finnish (FIN) AF: 0.0000209 AC: 1 AN: 47734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4988

European-Non Finnish (NFE) AF: 0.0000113 AC: 10 AN: 881824

Other (OTH) AF: 0.0000773 AC: 4 AN: 51738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000277 AC: 38 AN: 137166 Hom.: 0 Cov.: 34 AF XY: 0.000330 AC XY: 22 AN XY: 66764

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

African (AFR) AF: 0.000284 AC: 10 AN: 35208

American (AMR) AF: 0.000724 AC: 10 AN: 13812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3234

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4516

South Asian (SAS) AF: 0.000495 AC: 2 AN: 4040

European-Finnish (FIN) AF: 0.000209 AC: 2 AN: 9562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000172 AC: 11 AN: 63844

Other (OTH) AF: 0.00107 AC: 2 AN: 1862

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.416C>G (p.S139C) alteration is located in exon 1 (coding exon 1) of the KRTAP5-7 gene. This alteration results from a C to G substitution at nucleotide position 416, causing the serine (S) at amino acid position 139 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.2
DANN	Benign	0.66
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.022	T
M_CAP	Benign	0.00084	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.39	N
PhyloP100		-1.2
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.053
Sift	Benign	0.13	T
Sift4G	Benign	0.063	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.20		Loss of glycosylation at S139 (P = 0.0659);
MVP		0.043
MPC		0.011
ClinPred		0.035	T
GERP RS		-3.1
PromoterAI		0.0030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.071
gMVP		0.012
Mutation Taster		=100/0	polymorphism

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: rs765423098; hg19: chr11-71238762; COSMIC: COSV105336351; COSMIC: COSV105336351;