ENST00000674596.1:c.-129+166T>G

Variant names:

• chr17-19377693-A-C
• rs3866958
• ENST00000674596.1:c.-129+166T>G

Variant summary

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

The ENST00000674596.1(B9D1):​c.-129+166T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 260,162 control chromosomes in the GnomAD database, including 113,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61414 hom., cov: 33)
  • Exomes 𝑓: 0.98 (51837 hom.)
• Consequence: B9D1 ENST00000674596.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34
• Publications: 8 publications found

Genes affected

B9D1 (HGNC:24123): (B9 domain containing 1) This gene encodes a B9 domain-containing protein, one of several that are involved in ciliogenesis. Alterations in expression of this gene have been found in a family with Meckel syndrome. Meckel syndrome has been associated with at least six different genes. This gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Mar 2016]

MAPK7 (HGNC:6880): (mitogen-activated protein kinase 7) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is specifically activated by mitogen-activated protein kinase kinase 5 (MAP2K5/MEK5). It is involved in the downstream signaling processes of various receptor molecules including receptor type kinases, and G protein-coupled receptors. In response to extracelluar signals, this kinase translocates to cell nucleus, where it regulates gene expression by phosphorylating, and activating different transcription factors. Four alternatively spliced transcript variants of this gene encoding two distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-19377693-A-C is Benign according to our data. Variant chr17-19377693-A-C is described in ClinVar as [Benign]. Clinvar id is 1178285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B9D1	NM_001368769.2	c.-298+166T>G		intron_variant	Intron 1 of 6		NP_001355698.1
B9D1	XM_047435750.1	c.-96+166T>G		intron_variant	Intron 1 of 7		XP_047291706.1
B9D1	XM_047435751.1	c.-1456+166T>G		intron_variant	Intron 1 of 10		XP_047291707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B9D1	ENST00000674596.1	c.-129+166T>G		intron_variant	Intron 1 of 7			ENSP00000501877.1
B9D1	ENST00000642870.2	c.-298+166T>G		intron_variant	Intron 1 of 6			ENSP00000496409.2
B9D1	ENST00000477478.7	c.-298+166T>G		intron_variant	Intron 1 of 5	3		ENSP00000460939.2

Frequencies

GnomAD3 genomes AF: 0.890 AC: 135425 AN: 152118 Hom.: 61371 Cov.: 33

Gnomad AFR AF: 0.726

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.844

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.918

GnomAD4 exome AF: 0.979 AC: 105617 AN: 107926 Hom.: 51837 Cov.: 4 AF XY: 0.979 AC XY: 50549 AN XY: 51616

African (AFR) AF: 0.682 AC: 1499 AN: 2198

American (AMR) AF: 0.845 AC: 98 AN: 116

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 662 AN: 672

East Asian (EAS) AF: 0.850 AC: 362 AN: 426

South Asian (SAS) AF: 0.813 AC: 1729 AN: 2126

European-Finnish (FIN) AF: 1.00 AC: 30 AN: 30

Middle Eastern (MID) AF: 0.940 AC: 218 AN: 232

European-Non Finnish (NFE) AF: 0.991 AC: 97732 AN: 98654

Other (OTH) AF: 0.947 AC: 3287 AN: 3472

GnomAD4 genome AF: 0.890 AC: 135524 AN: 152236 Hom.: 61414 Cov.: 33 AF XY: 0.887 AC XY: 66010 AN XY: 74434

African (AFR) AF: 0.726 AC: 30131 AN: 41500

American (AMR) AF: 0.844 AC: 12914 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3434 AN: 3472

East Asian (EAS) AF: 0.853 AC: 4408 AN: 5166

South Asian (SAS) AF: 0.803 AC: 3876 AN: 4824

European-Finnish (FIN) AF: 0.983 AC: 10446 AN: 10624

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67182 AN: 68024

Other (OTH) AF: 0.919 AC: 1944 AN: 2116

Alfa AF: 0.910 Hom.: 12478

Bravo AF: 0.876

Asia WGS AF: 0.834 AC: 2901 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23804708) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.66
PhyloP100		-1.3
PromoterAI		0.17	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3866958; hg19: chr17-19281006;