NM_032524.2:c.279T>C

Variant names:

• chr17-41160413-A-G
• rs1249508757
• NM_032524.2:c.279T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_032524.2(KRTAP4-4):​c.279T>C​(p.Thr93Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000032 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP4-4 NM_032524.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• Publications: 0 publications found

Genes affected

KRTAP4-4 (HGNC:16928): (keratin associated protein 4-4) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-41160413-A-G is Benign according to our data. Variant chr17-41160413-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2647760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032524.2. 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
	KRTAP4-4	NM_032524.2	MANE Select	c.279T>C	p.Thr93Thr	synonymous	Exon 1 of 1	NP_115913.1	Q9BYR3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-4	ENST00000390661.5	TSL:6 MANE Select	c.279T>C	p.Thr93Thr	synonymous	Exon 1 of 1	ENSP00000375076.3	Q9BYR3

Frequencies

GnomAD3 genomes AF: 0.0000323 AC: 4 AN: 123756 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453120 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 723156

African (AFR) AF: 0.00 AC: 0 AN: 32468

American (AMR) AF: 0.0000226 AC: 1 AN: 44282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25670

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106926

Other (OTH) AF: 0.00 AC: 0 AN: 59652

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000323 AC: 4 AN: 123814 Hom.: 0 Cov.: 30 AF XY: 0.0000499 AC XY: 3 AN XY: 60068

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

African (AFR) AF: 0.0000624 AC: 2 AN: 32070

American (AMR) AF: 0.00 AC: 0 AN: 12536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3078

East Asian (EAS) AF: 0.00 AC: 0 AN: 3990

South Asian (SAS) AF: 0.00 AC: 0 AN: 3664

European-Finnish (FIN) AF: 0.000134 AC: 1 AN: 7452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000171 AC: 1 AN: 58356

Other (OTH) AF: 0.00 AC: 0 AN: 1746

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00143 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.40
DANN	Benign	0.37
PhyloP100		-1.4
PromoterAI		-0.0068	Neutral

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: rs1249508757; hg19: chr17-39316665;