rs2721176

Variant names:

• chr8-144474218-T-C
• rs2721176
• NM_003923.3:c.*20A>G

Variant summary

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

The NM_003923.3(FOXH1):​c.*20A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,519,038 control chromosomes in the GnomAD database, including 744,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73859 hom., cov: 34)
  • Exomes 𝑓: 0.99 (670576 hom.)
• Consequence: FOXH1 NM_003923.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.17
• Publications: 7 publications found

Genes affected

FOXH1 (HGNC:3814): (forkhead box H1) FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT. [provided by RefSeq, Jul 2008]

KIFC2 (HGNC:29530): (kinesin family member C2) Predicted to enable microtubule binding activity and microtubule motor activity. Predicted to be involved in microtubule-based movement and mitotic spindle assembly. Predicted to be located in cytoplasm. Predicted to be part of kinesin complex. Predicted to be active in microtubule cytoskeleton and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-144474218-T-C is Benign according to our data. Variant chr8-144474218-T-C is described in ClinVar as Benign. ClinVar VariationId is 259199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003923.3. 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
	FOXH1	NM_003923.3	MANE Select	c.*20A>G		3_prime_UTR	Exon 3 of 3	NP_003914.1	O75593
	KIFC2	NM_001369769.2	MANE Select	c.*829T>C		downstream_gene	N/A	NP_001356698.1	A0A2R8YEU8
	KIFC2	NM_145754.5		c.*768T>C		downstream_gene	N/A	NP_665697.1	Q96AC6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXH1	ENST00000377317.5	TSL:1 MANE Select	c.*20A>G		3_prime_UTR	Exon 3 of 3	ENSP00000366534.4	O75593
	FOXH1	ENST00000935088.1		c.*20A>G		3_prime_UTR	Exon 3 of 3	ENSP00000605147.1
	FOXH1	ENST00000935090.1		c.*20A>G		3_prime_UTR	Exon 3 of 3	ENSP00000605149.1

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149776 AN: 152196 Hom.: 73806 Cov.: 34

Gnomad AFR AF: 0.986

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.951

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.998

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.965 AC: 165617 AN: 171596 AF XY: 0.971

Gnomad AFR exome AF: 0.987

Gnomad AMR exome AF: 0.897

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.791

Gnomad FIN exome AF: 0.997

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.980

GnomAD4 exome AF: 0.990 AC: 1352452 AN: 1366724 Hom.: 670576 Cov.: 26 AF XY: 0.990 AC XY: 664836 AN XY: 671466

African (AFR) AF: 0.986 AC: 30133 AN: 30552

American (AMR) AF: 0.907 AC: 29439 AN: 32470

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 20764 AN: 20766

East Asian (EAS) AF: 0.753 AC: 29163 AN: 38746

South Asian (SAS) AF: 0.998 AC: 72282 AN: 72422

European-Finnish (FIN) AF: 0.996 AC: 48380 AN: 48554

Middle Eastern (MID) AF: 0.997 AC: 5147 AN: 5160

European-Non Finnish (NFE) AF: 1.00 AC: 1061622 AN: 1061884

Other (OTH) AF: 0.988 AC: 55522 AN: 56170

GnomAD4 genome AF: 0.984 AC: 149888 AN: 152314 Hom.: 73859 Cov.: 34 AF XY: 0.982 AC XY: 73156 AN XY: 74472

African (AFR) AF: 0.986 AC: 40999 AN: 41572

American (AMR) AF: 0.951 AC: 14556 AN: 15306

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.803 AC: 4144 AN: 5158

South Asian (SAS) AF: 0.997 AC: 4816 AN: 4830

European-Finnish (FIN) AF: 0.998 AC: 10605 AN: 10628

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68001 AN: 68028

Other (OTH) AF: 0.988 AC: 2089 AN: 2114

Alfa AF: 0.994 Hom.: 15845

Bravo AF: 0.978

Asia WGS AF: 0.943 AC: 3280 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Holoprosencephaly sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.35
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2721176; hg19: chr8-145699601; COSMIC: COSV56762547; COSMIC: COSV56762547;