6-10764226-C-T

Variant names:

• chr6-10764226-C-T
• rs547465110
• NM_001242957.3:c.*226G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_001242957.3(MAK):​c.*226G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 520,454 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (3 hom.)
• Consequence: MAK NM_001242957.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

MAK (HGNC:6816): (male germ cell associated kinase) The product of this gene is a serine/threonine protein kinase related to kinases involved in cell cycle regulation. Studies of the mouse and rat homologs have localized the kinase to the chromosomes during meiosis in spermatogenesis, specifically to the synaptonemal complex that exists while homologous chromosomes are paired. Mutations in this gene have been associated with ciliary defects resulting in retinitis pigmentosa 62. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TMEM14B (HGNC:21384): (transmembrane protein 14B) Enables identical protein binding activity. Involved in cerebral cortex development; neural precursor cell proliferation; and regulation of G1/S transition of mitotic cell cycle. Predicted to be integral component of membrane. Predicted to be active in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000272162 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.13).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000335 (51/152114) while in subpopulation SAS AF = 0.0106 (51/4802). AF 95% confidence interval is 0.0083. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242957.3. 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
	MAK	NM_001242957.3	MANE Select	c.*226G>A		3_prime_UTR	Exon 15 of 15	NP_001229886.1	P20794-2
	MAK	NM_005906.6		c.*226G>A		3_prime_UTR	Exon 14 of 14	NP_005897.1	A0A140VK28
	MAK	NM_001242385.2		c.*226G>A		3_prime_UTR	Exon 13 of 13	NP_001229314.1	P20794-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAK	ENST00000354489.7	TSL:5 MANE Select	c.*226G>A		3_prime_UTR	Exon 15 of 15	ENSP00000346484.3	P20794-2
	MAK	ENST00000474039.5	TSL:1	c.*226G>A		3_prime_UTR	Exon 14 of 14	ENSP00000476067.1	P20794-1
	MAK	ENST00000536370.6	TSL:1	c.*226G>A		3_prime_UTR	Exon 13 of 13	ENSP00000442221.2	P20794-3

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000880 AC: 324 AN: 368340 Hom.: 3 Cov.: 3 AF XY: 0.00131 AC XY: 254 AN XY: 193314

African (AFR) AF: 0.00 AC: 0 AN: 10776

American (AMR) AF: 0.00 AC: 0 AN: 13170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11654

East Asian (EAS) AF: 0.00 AC: 0 AN: 25766

South Asian (SAS) AF: 0.00928 AC: 319 AN: 34392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1632

European-Non Finnish (NFE) AF: 0.00000443 AC: 1 AN: 225700

Other (OTH) AF: 0.000183 AC: 4 AN: 21856

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41508

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000567

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis Pigmentosa, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.1
DANN	Benign	0.90
PhyloP100		1.7
Mutation Taster		=98/2	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: rs547465110; hg19: chr6-10764459;